Novel compounds and their use in therapy

ABSTRACT

This invention provides compounds of formula (I) and salts thereof, which have activity as inhibitors of N-myristoyl transferase (NMT). The invention also relates to uses of such compounds as medicaments, in particular in the treatment of a disease or disorder in which inhibition of N-myristoyl transferase provides a therapeutic or prophylactic effect, including protozoan infections (such as malaria and leishmaniasis), viral infections (such as human rhinovirus and HIV), and hyperproliferative disorders (such as B-cell lymphoma).

FIELD OF INVENTION

This invention relates to compounds of formula (I) and salts thereofwhich have activity as inhibitors of N-myristoyl transferase (NMT). Theinvention also relates to uses of such compounds as medicaments, inparticular in the treatment of a disease or disorder in which inhibitionof N-myristoyl transferase provides a therapeutic or prophylacticeffect. Such diseases include protozoan infections (such as malaria andleishmaniasis), viral infections (such as human rhinovirus and HIV), andhyperproliferative disorders (such as B-cell lymphoma).

BACKGROUND TO THE INVENTION

N-myristoyl transferase (NMT) is a monomeric enzyme, which is ubiquitousin eukaryotes. NMT catalyses an irreversible co-translational transferof myristic acid (a saturated 14-carbon fatty acid) frommyristoyl-Coenzyme A (myr-CoA) to a protein substrate containing anN-terminal glycine with formation of an amide bond (Farazi, T. A., G.Waksman, and J. I. Gordon, J. Biol. Chem., 2001. 276 (43): p.39501-39504). N-myristoylation by NMT follows an ordered Bi—Bimechanism. Myr-CoA binds to NMT in the first NMT binding pocket prior tothe binding of a protein substrate (Rudnick, D. A., C. A. McWherter, W.J. Rocque, et al., J. Biol. Chem., 1991. 266 (15): p. 9732-9739.). Thebound myr-CoA facilitates the opening of a second binding pocket wherethe protein substrate binds. Following binding of the protein substrate,transfer of myristate to the protein substrate takes place via anucleophilic addition-elimination reaction, finally with the release ofCoA and the myristoylated protein.

NMT plays a key role in protein trafficking, mediation ofprotein-protein interactions, stabilization of protein structures andsignal transduction in living systems. Inhibition of the NMT enzyme hasthe potential to disrupt multi-protein pathways, which is an attractivecharacteristic to reduce the risk of the development of resistance in,for example, treatment or prophylaxis of microbial infections andhyperproliferative disorders.

Biochemical analysis has shown high conservation of myr-CoA bindingsites, but divergent peptide binding specificities between human andfungal and parasitic NMTs (Johnson, D. R., R. S. Bhatnagar, J. I.Gordon, et al., Annu. Rev. Biochem., 1994. 63: p. 869-914.). As aconsequence, NMT can be viewed as a target with the potential for thedevelopment of selective non-peptidic inhibitors.

NMT fungal and mammalian enzymes from various sources have been wellcharacterized, see for example the following references: Saccharomycescerevisiae (Duronio, R. J., D. A. Towler, R. O. Heuckeroth, et al.,Science, 1989. 243 (4892): p. 796-800), Candida albicans (Wiegand, R.C., C. Carr, J. C. Minnerly, et al., J. Biol. Chem., 1992. 267 (12): p.8591-8598) and Cryptococcus neoformans (Lodge, J. K., R. L. Johnson, R.A. Weinberg, et al., J. Biol. Chem., 1994. 269 (4): p. 2996-3009), humanNMT1 (Mcllhinney, R. A. J. and K. McGlone, Exp. Cell Res., 1996. 223: p.348-356) and human NMT2 (Giang, D. K. and B. F. Cravatt, J. Biol. Chem.,1998. 273: p. 6595-6598).

NMT has also been characterised in protozoan parasites. See for examplethe following references: Plasmodium falciparum (Pf) (Gunaratne, R. S.,M. Sajid, I. T. Ling, et al., Biochem. J., 2000. 348: p. 459-463),Plasmodium vivax (Pv), Leishmania major (Lm) (Price, H. P., M. R. Menon,C. Panethymitaki, et al., J. Biol. Chem., 2003. 278 (9): p. 7206-7214.),Leishmania donovani (Ld) (Branningan, J. A., B. A. Smith, Z. Yu, et al.,J. Mol. Biol., 2010. 396: p. 985-999) and Trypanosoma brucei (Tb)(Price, H. P., M. R. Menon, C. Panethymitaki, et al., J. Biol. Chem.,2003. 278 (9): p. 7206-7214.

Several myristoylated proteins have been observed in protozoans andtheir functions have been determined. These proteins and the processesin which they are involved suggest that N-myristoylation may play a rolein multiple pathways in the biology of parasites. Inhibition ofmyristoylation could thus disrupt multiple pathways. The potential forthe development of resistance should thus be smaller than for some othertargets. To date, only a single isoform of NMT has been found in eachprotozoan organism investigated. If it is correct that there is only asingle isoform, then that will also assist in reducing the potential forthe development of resistance.

Inhibition of human NMT has also been suggested as a target for treatingor preventing various diseases or disorders, for examplehyperproliferative disorders (cancers, e.g. human colorectal cancer,gallbladder carcinoma, brain tumors, lymphomas such as B-cell lymphoma)(Resh M D. 1993. Biochern. Biophys. Acta 1115, 307-22), and viralinfections such as HIV (Gottlinger H G, Sodroski J G, Haseltine W A.1989. Proc. Nat. Acad. Sci. USA 86:5781-85; Bryant M L, Ratner L. 1990.Proc. Natl. Acad. Sci. USA 87:523-27) and human rhinovirus (HRV) (DavisM P, Bottley, G, Beales L P, Killington, R A, Rowlands D J, Tuthill, TJ, 2008 Journal of Virology 82 4169-4174).

As described above, there are two binding pockets in NMT. One is themyr-CoA binding pocket and the other is the peptide binding pocket. MostNMT inhibitors reported to date target the peptide binding pocket. MostNMT inhibitors developed to date have been targeted to fungalN-myristoyl transferases.

Compounds active as inhibitors of NMT have previously been disclosed,see for example WO00/37464 (Roche), WO2010/026365 (University ofDundee), and WO2013/083991 (Imperial Innovations Limited). In addition,Bell et al disclosed the results of a high throughput screening studycarried out to identify inhibitors of NMT, and disclosed the compoundN,N-dimethyl-1-(5-(o-tolyl)-1H-indazol-3-yl)methanamine as havingactivity against Plasmodium falciparum NMT (PLoS Neglected TropicalDiseases, 2012, 6, e1625). A further indazole-containing analogue(1-(5-(4-fluoro-2-methylphenyl)-1H-indazol-3-yl)-N,N-dimethylmethanamine)was disclosed as part of a presentation “Selective inhibitors ofprotozoan protein N-myristoyl transferases” on 18 Sep. 2012 during aSymposium “Emerging Paradigms in Anti-Infective Drug Design” held at theLondon School of Hygiene and Tropical Medicine.

However, there remains a need in the art for further compounds active asinhibitors of N-myristoyl transferase.

SUMMARY OF THE INVENTION

The invention provides an inhibitor of N-myristoyl transferase (NMT)which is a compound of formula (I) or a salt thereof,

wherein:

Y is selected from the group consisting of —CH—, —C(R²)— and —N—;

R¹ is a group of formula —X-L-A;

X is selected from the group consisting of —O—, —N(H)— and —S—, or isabsent;

L is selected from the group consisting of —(CHR¹²)_(m)— and—(CHR¹²)_(m)O—, or is absent;

m is 1, 2 or 3;

A is a 6-10-membered aromatic carbocycle or a 5-10-membered aromaticheterocycle, said aromatic carbocycle or heterocycle being optionallysubstituted with 1, 2, or 3 substituents each independently selectedfrom the group consisting of —F, —Cl, —Br, —OCH₃, —OCF₃, —CN, —C₁₋₆alkyloptionally substituted by up to 3 halogen, hydroxyl, or —OC₁₋₄alkylgroups, —S(O)C₁₋₄alkyl, —S(O)₂C₁₋₄alkyl, —C(O)N(R⁹)₂,—C(O)N(R¹³)C₁₋₄alkylOC₁₋₄alkyl, —C(O)N(C₁₋₄alkylOC₁₋₄ alkyl)₂,—CH₂C(O)N(R⁹)₂, —CH₂C(O)N(R¹³)C₁₋₄alkylOC₁₋₄alkyl,—CH₂C(O)N(C₁₋₄alkylOC₁₋₄alkyl)₂, —S(O)₂NHC₁₋₄alkyl, —S(O)₂N(C₁₋₄alkyl)₂,—NHC₁₋₄alkyl, —N(C₁₋₄alkyl)₂, —NHC(O)C₁₋₄ alkyl, —NHC(O)CF₃,—NHS(O)₂C₁₋₄alkyl, CH₂N(R¹³)₂, CH₂N(R¹³)C(O)C₁₋₄alkyl,CH₂N(R¹³)S(O)₂C₁₋₄alkyl, —CH₂S(O)₂C₁₋₄alkyl, and CO₂H;

s is 0, 1, 2, or 3;

each R² is independently selected from the group consisting of —F, —Cl,—Br, —OCH₃, —OCF₃, —CN, —C₁₋₄alkyl optionally substituted by up to 3halogen or hydroxyl groups, —S(O)C₁₋₄alkyl, —S(O)₂C₁₋₄alkyl,—S(O)₂NHC₁₋₄alkyl, —S(O)₂N(C₁₋₄alkyl)₂, —NHC₁₋₄alkyl, —N(C₁₋₄alkyl)₂,—NHC(O)C₁₋₄alkyl, —NHC(O)CF₃, and —NHS(O)₂C₁₋₄alkyl;

E, J and G are each independently nitrogen or C(R⁷);

K is carbon or nitrogen;

when K is carbon, either Q is N(R¹) and M is nitrogen or C(R⁷), or Q isnitrogen and M is N(R⁸);

when K is nitrogen, Q is nitrogen or C(R⁷) and M is nitrogen or C(R⁷);

and further wherein at least 2 of E, J, G, K, Q and M are selected fromthe group consisting of carbon and C(R⁷);

q is 0 or 1;

R³ is hydrogen or methyl; R⁴ is hydrogen or methyl;

R⁵ is hydrogen or C₁₋₆alkyl optionally substituted by up to 3 —F, —Cl,—Br, —OH, —OCH₃, —OCF₃ or —CN groups; R⁶ is hydrogen or C₁₋₆alkyloptionally substituted by up to 3 —F, —Cl, —Br, —OH, —OCH₃, —OCF₃ or —CNgroups; or the R⁵ and R⁶ groups and the N they are bonded to form a 4 to7 membered non-aromatic heterocycle, the heterocycle optionallycomprising 1 or 2 further heteroatoms selected from N, O and S,optionally substituted by up to 3 —F, —Cl, —Br, —OH, —OCH₃, —OCF₃ or —CNgroups;

when present R¹⁰ is hydrogen or methyl;

when present R¹¹ is hydrogen or methyl;

or the R³ group and the R⁵ group and the intervening atoms form a 3 to 7membered non-aromatic heterocycle composed of the intervening atoms andbond, or the intervening atoms and —(CHR^(a))_(r)—; or the R¹⁰ group andthe R⁵ group and the intervening atoms form a 3 to 7 memberednon-aromatic heterocycle composed of the intervening atoms and—(CHR^(a))_(r)—;

r is 1, 2, 3, 4 or 5; R^(a) is hydrogen or methyl;

each R⁷ is independently selected from the group consisting of hydrogen,halogen, C₁₋₄ alkoxy, and C₁₋₄alkyl optionally substituted with 1, 2 or3 halogens; and R⁸ is selected from the group selected from hydrogen andC₁₋₄alkyl;

each R⁹ is independently selected from the group consisting of hydrogenand C₁₋₄alkyl, or two R⁹ groups and the N they are bonded to form a 4 to7 membered non-aromatic heterocycle, the heterocycle optionallycomprising 1 or 2 further heteroatoms selected from N, O and S;

each R¹² is independently selected from the group consisting ofhydrogen, C₁₋₆alkyl optionally substituted by up to 3 —F, —Cl, —Br, I,—OH, —OCH₃, —OCF₃ or —CN groups, C₁₋₆alkenyl optionally substituted byup to 3 —F, —Cl, —Br, I, —OH, —OCH₃, —OCF₃ or —CN groups, andC₁₋₆alkynyl optionally substituted by up to 3 —F, —Cl, —Br, I, —OH,—OCH₃, —OCF₃ or —CN groups; and each R¹³ is independently selected fromthe group consisting of hydrogen and C₁₋₄alkyl.

The compounds of the invention have surprisingly been found to haveactivity as inhibitors of N-myristoyl transferase.

The invention also provides a pharmaceutical composition comprising anNMT inhibitor according to the invention and a pharmaceuticallyacceptable carrier.

The invention also provides an NMT inhibitor or a pharmaceuticalcomposition according to the invention for use as a medicament.

The invention also provides an NMT inhibitor or a pharmaceuticalcomposition according to the invention for use in the prevention ortreatment of a disease or disorder in which inhibition of N-myristoyltransferase provides a therapeutic or prophylactic effect.

The invention also provides use of an NMT inhibitor according to theinvention for the manufacture of a medicament for the prevention ortreatment of a disease or disorder in which inhibition of N-myristoyltransferase provides a therapeutic or prophylactic effect.

The invention also provides a method of treating or preventing a diseaseor disorder in which inhibition of N-myristoyl transferase provides atherapeutic or prophylactic effect in a mammal, which comprisesadministering to the mammal a therapeutically effective amount of an NMTinhibitor or pharmaceutical composition according to the invention.

The invention also provides a kit of parts comprising: (a) a firstpharmaceutical composition comprising an NMT inhibitor according to theinvention and a pharmaceutically acceptable carrier; and (b) a secondpharmaceutical composition comprising a further therapeutic agent,preferably a further N-myristoyl transferase inhibitor, and apharmaceutically acceptable carrier.

BRIEF DESCRIPTION OF THE DRAWINGS

FIGS. 1A-C show tables containing NMT (N-myristoyl transferase) IC₅₀(μM) and EC₅₀ (μM) values for Example compounds 1 to 51, 53 to 58, 60,62, 63, and 66 to 101 of the invention tested for their ability toinhibit NMT of various species. Details of the assay are described at(a) below. The table further shows EC50 (μM) values for certain Examplecompounds of the invention tested for their ability to inhibitPlasmodium falciparum viability (Pf strains 3D7 or NF54 (NF54 resultsshown in bold text), details of which are described at (b) below. Thetable also shows the EC₅₀ (μM) results of the P. berghei liver stageassay for certain example compounds, details of which are described at(g) below. The table further shows the results of how certain Examplecompounds of the invention performed in a mouse malaria model. Thepercentage reduction in the parasite burden for mice treated with acompound of the invention over control mice is indicated in the table.Details of the mouse malaria model are provided at (c) below. The tablealso shows EC₅₀ values for certain Example compounds of the inventiontested for their ability to inhibit metabolic activity in BL-41 cells.Details of the assay are described at (d) below.

FIG. 2 shows a representation of a 96-well plate used to determine theinhibitory effects of Example compounds of the invention in a metabolicactivity assay using HeLa and/or BL-41 cells.

FIG. 3 shows a table containing EC₅₀ values for Example compounds 30 and33 of the invention tested for their ability to inhibit metabolicactivity in HeLa cells. Details of the assay are described at (d) below.

FIG. 4 shows the effect of Example 30 on rhinovirus production in HeLacells. Details of the assay are described at (e) below.

FIG. 5 a-5 c show the results for Examples 30, 35, 49 and 50 when testedin a rhinovirus replication assay in the human HeLa Ohio cell line,details of which are described at (f) below. FIGS. 5 a and 5 b show thevirus-induced cytopathic effect (CPE) measured by a Metabolic ActivityAssay (MTS assay) 2 days post-infection. The cell viability of theinhibitor-treated but uninfected cells was measured in parallel by MTS 2days post-treatment, and the results are shown in FIG. 5 c.

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides compounds that are NMT inhibitors. Theterm “NMT inhibitor” as used herein is intended to cover any moietywhich binds to NMT and inhibits its activity. The inhibitors may act ascompetitive inhibitors, or partial competitive inhibitors. The inhibitormay bind to NMT at the myr-CoA binding pocket or at the peptide bindingpocket (or inhibit NMT through another mechanism). Compounds of thepresent invention preferably bind and inhibit NMT through the peptidebinding pocket.

Definitions

The following definitions apply to the terms as used throughout thisspecification, unless otherwise limited in specific instances.

As used herein, the term “alkyl” means both straight and branched chainsaturated hydrocarbon groups. Examples of alkyl groups include methyl,ethyl, n-propyl, iso-propyl, n-butyl, t-butyl, i-butyl, sec-butyl,pentyl and hexyl groups. Among unbranched alkyl groups, there arepreferred methyl, ethyl, n-propyl, iso-propyl, n-butyl groups. Amongbranched alkyl groups, there may be mentioned t-butyl, i-butyl,1-ethylpropyl and 1-ethylbutyl groups.

As used herein, the term “alkylene” means both straight and branchedchain divalent hydrocarbon radical. Examples of alkyl groups includemethylene, ethylene, n-propylene, iso-propylene, n-butylene, t-butylene,i-butylene, sec-butylene, pentylene and hexylene groups. Amongunbranched alkyl groups, there are preferred methylene, ethylene,n-propylene, iso-propylene, n-butylene groups. Among branched alkylgroups, there may be mentioned t-butylene, i-butylene, 1-ethylpropyleneand 1-ethylbutylene groups

As used herein, the term “alkenyl” means both straight and branchedchain unsaturated hydrocarbon groups with at least one carbon carbondouble bond. Examples of alkenyl groups include ethenyl, propenyl,butenyl, pentenyl and hexenyl. Preferred alkenyl groups include ethenyl,1-propenyl, 2-propenyl and but-2-enyl.

As used herein, the term “alkenylene” refers to a straight or branchedchain divalent hydrocarbon radical with at least one carbon carbondouble bond. Examples of alkenylene groups include ethenylene,1-propenylene, 2-propenylene and but-2-enylene.

As used herein, the term “alkynyl” means both straight and branchedchain unsaturated hydrocarbon groups with at least one carbon carbontriple bond. Examples of alkynyl groups include ethynyl, propynyl,butynyl, pentynyl and hexynyl. Preferred alkynyl groups include ethynyl,1-propynyl and 2-propynyl.

As used herein, the term “alkynylene” means both straight and branchedchain divalent hydrocarbon radical with at least one carbon carbontriple bond. Examples of alkynylene groups include ethynylene,1-propynylene, 2-propynylene, butynylene, pentynylene and hexynylene.

As used herein, the term “carbocycle” is intended to mean any 3- to13-membered carbon ring system, which may be saturated, partiallyunsaturated, or aromatic. The carbon ring system may be monocyclic orcontain more than one ring (e.g. the ring system may be bicyclic).Examples of monocyclic saturated carbocycles include cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl. Examplesof bicyclic saturated carbocycles include bicyclooctane, bicyclononane,bicyclodecane (decalin) and bicyclooctane. A further example of asaturated carbocycle is adamantane. Examples of monocyclic non-saturatedcarbocycles include cyclobutene, cyclopentene, cyclopentadiene,cyclohexene. Examples of aromatic carbocycles include phenyl andnaphthyl. Further examples of aromatic carbocycles includetetrahydronaphthyl (tetralin) and indane.

As used herein, the term “cycloalkyl” means a saturated group in a ringsystem. A cycloalkyl group can be monocyclic or bicyclic. A bicyclicgroup may, for example, be fused or bridged. Examples of monocycliccycloalkyl groups include cyclopropyl, cyclobutyl and cyclopentyl. Otherexamples of monocyclic cycloalkyl groups are cyclohexyl, cycloheptyl andcyclooctyl. Examples of bicyclic cycloalkyl groups include bicyclo [2.2.1]hept-2-yl Preferably, the cycloalkyl group is monocyclic.

As used herein, the term “cycloalkylene” means a 3- to 7-memberednon-aromatic alicyclic divalent hydrocarbon radical, Examples ofcycloalkylene include cyclopropylene, cyclobutylene and cyclopentylene.Other examples of monocyclic cycloalkyl groups are cyclohexylene andcycloheptylene. Preferably, the cycloalkylene group is monocyclic.

As used herein, the term “halogen” or “halo” means fluorine, chlorine,bromine or iodine.

Fluorine, chlorine and bromine are particularly preferred.

As used herein, the term “haloalkyl” means an alkyl group having ahalogen substituent, the terms “alkyl” and “halogen” being understood tohave the meanings outlined above.

Similarly, the term “dihaloalkyl” means an alkyl group having twohalogen substituents and the term “trihaloalkyl” means an alkyl grouphaving three halogen substituents. Examples of haloalkyl groups includefluoromethyl, chloromethyl, bromomethyl, fluoromethyl, fluoropropyl andfluorobutyl groups; examples of dihaloalkyl groups includedifluoromethyl and difluoroethyl groups; examples of trihaloalkyl groupsinclude trifluoromethyl and trifluoroethyl groups.

As used herein, the term “heterocyclyl” (or heterocycle) means anaromatic or a non-aromatic cyclic group of carbon atoms wherein from oneto four of the carbon atoms is/are replaced by one or more heteroatomsindependently selected from nitrogen, oxygen or sulfur. A heterocyclyl(or heterocycle) group may, for example, be monocyclic or bicyclic. In abicyclic heterocyclyl (or heterocycle) group there may be one or moreheteroatoms in each ring, or only in one of the rings. A heteroatom maybe S, O or N, and is preferably 0 or N.

Examples of monocyclic non-aromatic heterocyclyl (or heterocycle)include aziridinyl, azetidinyl, pyrrolidinyl, imidazolidinyl,pyrazolidinyl, piperidinyl, piperazinyl, tetrahydrofuranyl,tetrahydropyranyl, morpholinyl, thiomorpholinyl and azepanyl.

Examples of monocyclic aromatic heterocyclyl (or heterocycle) groupsinclude furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl,oxadiazolyl, thiadiazolyl, pyridyl, triazolyl, triazinyl, tetrazolyl,pyridazyl, isothiazolyl, isoxazolyl, pyrazinyl, pyrazolyl andpyrimidinyl.

Examples of bicyclic aromatic heterocyclyl groups (or heterocycle)include quinoxalinyl, quinazolinyl, pyridopyrazinyl, benzoxazolyl,benzothiophenyl, benzimidazolyl, naphthyridinyl, quinolinyl,benzofuranyl, indolyl, benzothiazolyl, oxazolyl[4,5-b]pyridiyl,pyridopyrimidinyl, isoquinolinyl and benzodroxazole. Further examples ofbicyclic aromatic heterocyclyl groups include those in which one of therings is aromatic and the other is non-aromatic, such asdihydrobenzofuranyl, indanyl, indolinyl, isoindolinyl,tetrahydroisoquinolinyl, tetrahydroquinolyl and benzoazepanyl.

The compounds of the invention may contain chiral (asymmetric) centers.The molecule as a whole may be chiral. The individual stereoisomers(enantiomers and diastereoisomers) and mixtures of these are within thescope of the present invention.

For the avoidance of doubt, an embodiment or preferred aspect of any onefeature of the NMT inhibitors of the invention may be combined with anyembodiment or preferred aspect of another feature of the NMT inhibitorsof the invention to create a further embodiment.

In one preferred embodiment of the invention, X is selected from thegroup consisting of —O—, —N(H)— and —S—. In another preferred embodimentL is selected from the group consisting of —(CHR¹²)_(m)— and—(CHR¹²)_(m)O—. Most preferably X is selected from the group consistingof —O—, —N(H)— and —S— and L is selected from the group consisting of—(CHR¹²)_(m)— and —(CHR¹²)_(m)O—.

In another preferred embodiment E, J, G and M are each C(R⁷), and K andQ are each nitrogen. In another preferred embodiment q is 1, R¹⁰ ishydrogen and R¹¹ is hydrogen. In a especially preferred embodiment, q is1, R¹⁰ is hydrogen and R¹¹ is hydrogen and E, J, G and M are each C(R⁷),and K and Q are each nitrogen.

In one preferred embodiment of the invention, A is a 6-10-memberedaromatic carbocycle or a 5-10-membered aromatic heterocycle, saidaromatic carbocycle or heterocycle being optionally substituted with 1,2, or 3 substituents each independently selected from the groupconsisting of —F, —Cl, —Br, —OCH₃, —OCF₃, —CN, —C₁₋₆alkyl optionallysubstituted by up to 3 halogen, hydroxyl, or —OC₁₋₄alkyl groups,—S(O)C₁₋₄alkyl, —S(O)₂C₁₋₄alkyl, —C(O)N(R⁹)₂, —CH—₂C(O)N(R⁹)₂,—S(O)₂NHC₁₋₄alkyl, —S(O)₂N(C₁₋₄alkyl)₂, —NHC₁₋₄alkyl, —N(C₁₋₄alkyl)₂,—NHC(O)C₁₋₄alkyl, —CH₂NHC(O)C₁₋₄alkyl, —NHC(O)CF₃ and —NHS(O)₂C₁₋₄alkyl.

In another preferred embodiment of the invention, A is a 6-10-memberedaromatic carbocycle or a 5-10-membered aromatic heterocycle, saidaromatic carbocycle or heterocycle being optionally substituted with 1,2, or 3 substituents each independently selected from the groupconsisting of —F, —Cl, —Br, —OCH₃, —OCF₃, —CN, —C₁₋₆alkyl optionallysubstituted by up to 3 halogen, hydroxyl, or —OC₁₋₄alkyl groups,—S(O)C₁₋₄alkyl, —S(O)₂C₁₋₄alkyl, —C(O)N(R⁹)₂, —CH₂C(O)N(R⁹)₂,—S(O)₂NHC₁₋₄alkyl, —S(O)₂N(C₁₋₄alkyl)₂, —NHC₁₋₄alkyl, —N(C₁₋₄alkyl)₂,—NHC(O)C₁₋₄alkyl, —CH₂NHC(O)C₁₋₄alkyl, —NHC(O)CF₃, —NHS(O)₂C₁₋₄alkyl,CH₂NH₂, CH₂NHC₁₋₄alkyl, CH₂NC₁₋₄alkylC(O)C₁₋₄alkyl, CH₂NHS(O)₂C₁₋₄alkyl,—CH₂S(O)₂C₁₋₄alkyl, CH₂NC₁₋₄alkylS(O)₂C₁₋₄alkyl.

In one preferred embodiment of the NMT inhibitor of the invention, thecompound has the formula (IA)

(for example

wherein R¹, R², s, E, J G, K, Q, M, q, R³, R⁴, R⁵ and R⁶, R⁷, R⁸, R⁹,R¹⁰ and R¹¹ are as defined in formula (I).

In another preferred embodiment of the NMT inhibitor of the invention,the compound has the formula (IB)

(for example

wherein R¹, R², s, E, J, G, K, Q, M, R³, R⁴, R⁵ and R⁶ are as defined informula (I).

In one preferred embodiment of the NMT inhibitor of the invention, theNMT inhibitor has the formula (IA*):

wherein each R^(2*) is independently selected from the group consistingof —F, —Cl, —Br, —OCH₃, —OCF₃, —CN, —C₁₋₄alkyl optionally substituted byup to 3 halogen or hydroxyl groups, —S(O)C₁₋₄ alkyl, —S(O)₂C₁₋₄alkyl,—S(O)₂NHC₁₋₄alkyl, —S(O)₂N(C₁₋₄alkyl)₂, —NHC₁₋₄alkyl, —N(C₁₋₄alkyl)₂,—NHC(O)C₁₋₄alkyl, —NHC(O)CF₃, and —NHS(O)₂C₁₋₄alkyl (preferably selectedfrom the group consisting of —F, —Cl, —Br, —OCH₃, —OCF₃, —CN, —C₁₋₄alkyloptionally substituted by up to 3 halogen or hydroxyl groups; morepreferably selected from the group consisting of —F and —Cl; mostpreferably —F); and R²** is selected from the group consisting of —H,—F, —Cl, —Br, —OCH₃, —OCF₃, —CN, —C₁₋₄alkyl optionally substituted by upto 3 halogen or hydroxyl groups, —S(O)C₁₋₄alkyl, —S(O)₂C₁₋₄alkyl,—S(O)₂NHC₁₋₄alkyl, —S(O)₂N(C₁₋₄alkyl)₂, —NHC₁₋₄alkyl, —N(C₁₋₄alkyl)₂,—NHC(O)C₁₋₄alkyl, —NHC(O)CF₃, and —NHS(O)₂C₁₋₄alkyl (preferably selectedfrom the group consisting of —H, —F, —Cl, —Br, —OCH₃, —OCF₃, —CN,—C₁₋₄alkyl optionally substituted by up to 3 halogen or hydroxyl groups;more preferably selected from the group consisting of —H, —F and —Cl).More preferably the compound has the formula (IA***):

Compounds of formula (IA*) and (IA***) are surprisingly highly active,and their high potency makes them especially viable for use as HsNMTinhibitors.

In another embodiment the NMT inhibitor of the invention is a compoundof formula (I) (or for example (IA) or (IA″)), with the proviso thecompound is not a compound of formula (IA*). In another embodiment theNMT inhibitor of the invention is a compound of formula (I) (or forexample (IA) or (IA″)), with the proviso the compound is pot a compoundof formula (IA***).

In another embodiment the NMT inhibitor of the invention is a compoundof formula (IA**) or (IB):

wherein s is 0, 1 or 2 for formula (IA**); and s is 0, 1, 2 or 3 for(IB).

At least two of the variable ring atoms in the core bicyclic moiety offormula (I) are carbon. In other words, at least two of E, J, G, K, Qand M are selected from the group consisting of C(R⁷) and carbon (withit being possible for E, J, G, Q and M to be C(R⁷), and it beingpossible for K to be carbon).

At least one of the variable ring atoms in the core bicyclic moiety offormula (I) is nitrogen. In other words at least one of E, J, G, K, Qand M is selected from the group consisting of nitrogen and N(R⁸). Byway of explanation, K is either carbon or nitrogen and, where K iscarbon, either either Q is N(R⁸) and M is nitrogen or C(R⁷), or Q isnitrogen and M is N(R⁸).

In one preferred embodiment of the NMT inhibitor of the invention, E, Jand G are each C(R⁷), K is carbon, Q is N(R⁸), and M is nitrogen.

In one preferred embodiment of the NMT inhibitor of the invention, E, Jand G are each C(R⁷), and K, Q and M are each nitrogen.

In one preferred embodiment of the NMT inhibitor of the invention, E andG are each C(R⁷), and J, K, Q and M are each nitrogen.

In one preferred embodiment of the NMT inhibitor of the invention, J andG are each C(R⁷), and E, K, Q and M are each nitrogen.

In one preferred embodiment of the NMT inhibitor of the invention, E, J,G and M are each C(R⁷), and K and Q are each nitrogen.

More preferably, E, J and G are each C(R⁷), K is carbon, Q is N(R⁸), andM is nitrogen; E, J and G are each C(R⁷), and K, Q and M are eachnitrogen; or E, J, G and M are each C(R⁷), and K and Q are eachnitrogen. Most preferably E, J and G are each C(R⁷), K is carbon, Q isN(R⁸), and M is nitrogen; or E, J and G are each C(R⁷), and K, Q and Mare each nitrogen.

In certain embodiments Y is —CH— or —C(R^(2′))—; preferably Y is —CH—.In another embodiment Y is —N—.

In one preferred embodiment, s is 0, 1 or 2, and, where present, each R²is independently selected from the group consisting of —F, —Cl, —Br,—OCH₃, —OCF₃, —CN, and —C₁₋₄alkyl optionally substituted by up to 3halogen or hydroxyl groups. More preferably R² is F or Cl.

In one preferred embodiment, A is an aromatic carbocycle or heterocycleselected from the group consisting of phenyl, pyridinyl, quinolinyl,imidazolyl, benzimidazolyl, pyrazolyl, thiazolyl, 1,2,3-triazolyl and1,2,4-triazolyl, said aromatic carbocycle or heterocycle beingoptionally substituted with 1, 2, or 3 groups independently selectedfrom the group consisting of —C₁₋₄alkyl (for example methyl), whereineach —C₁₋₄alkyl is optionally substituted by up to 3 halogen, hydroxylor —OC₁₋₄alkyl groups; C(O)N(R⁹)₂ (for example —C(O)N(H)C₁₋₄alkyl or—C(O)N(R⁹)₂ wherein the two R⁹ groups and the N they are bonded to forma 4 to 7 membered non-aromatic heterocycle, the heterocycle optionallycomprising 1 or 2 further heteroatoms selected from N, O and S (forexample wherein the two R⁹ and the N they are bonded to form amorpholine or pyrrolidine ring)), —CH₂C(O)N(R⁹)₂ (for example—CH—₂C(O)N(H)C₁₋₄alkyl), —CH₂C(O)N(R⁹)₂ (for example—CH₂C(O)N(H)C₁₋₄alkyl), —C(O)N(R¹³)C₁₋₄alkylOC₁₋₄alkyl (for example—C(O)N(H)C₁₋₄alkylOC₁₋₄alkyl), —N(R⁹)C(O)C₁₋₄alkyl, —CH₂N(R¹³)₂,CH₂N(R⁹)C(O)C₁₋₄alkyl or CH₂N(R¹³)S(O)₂C₁₋₄alkyl; and more preferablyC(O)N(R⁹)₂ (for example —C(O)N(H)C₁₋₄alkyl), or —CH₂C(O)N(R⁹)₂ (forexample —CH—₂C(O)N(H)C₁₋₄alkyl). Preferably A is selected from the groupconsisting optionally substituted pyrazolyl and thiazolyl.

In one preferred embodiment, A is optionally substituted with 1, 2, or 3groups independently selected from the group consisting of —C₁₋₄alkyl(for example methyl), wherein each —C₁₋₄alkyl is optionally substitutedby up to 3 halogen, hydroxyl or —OC₁₋₄alkyl groups (preferably one—OC₁₋₄alkyl group; more preferably one —OCH₃ group); C(O)N(R⁹)₂ (forexample —C(O)N(H)C₁₋₄alkyl or —C(O)N(R⁹)₂ wherein the two R⁹ groups andthe N they are bonded to form a 4 to 7 membered non-aromaticheterocycle, the heterocycle optionally comprising 1 or 2 furtherheteroatoms selected from N, O and S (for example wherein the two R⁹ andthe N they are bonded to form a morpholine or pyrrolidine ring)),—CH₂C(O)N(R⁹)₂ (for example —CH—2C(O)N(H)C₁₋₄alkyl), —CH₂C(O)N(R⁹)₂ (forexample —CH₂C(O)N(H)C₁₋₄alkyl), —C(O)N(R¹³)C₁₋₄alkylOC₁₋₄alkyl (forexample —C(O)N(H)C₁₋₄alkylOC₁₋₄alkyl), —N(R⁹)C(O)C₁₋₄alkyl, —CH₂N(R¹³)₂,CH₂N(R⁹)C(O)C₁₋₄alky or CH₂N(R¹³)S(O)₂C₁₋₄alkyl I; preferably C(O)N(R⁹)₂(for example —C(O)N(H)C₁₋₄alkyl), —CH₂C(O)N(R⁹)₂ (for example—CH₂C(O)N(H)C₁₋₄alkyl). Preferably A is selected from the groupconsisting optionally substituted pyrazolyl and thiazolyl.

In certain preferred embodiments, A is optionally substituted with 1, 2,or 3 groups independently selected from the group consisting of—C₁₋₄alkyl (for example methyl), wherein each —C₁₋₄alkyl is optionallysubstituted by up to 3 halogen, hydroxyl or —OC₁₋₄alkyl groups(preferably one —OC₁₋₄alkyl group; more preferably one —OCH₃ group);—C(O)N(H)C₁₋₄alkyl (for example —C(O)N(H)CH₃) or —C(O)N(R⁹)₂ wherein thetwo R⁹ groups and the N they are bonded to form a 4 to 7 memberednon-aromatic heterocycle, the heterocycle optionally comprising 1 or 2further heteroatoms selected from N, O and S (for example wherein thetwo R⁹ and the N they are bonded to form a morpholine or pyrrolidinering), —CH₂C(O)N(H)C₁₋₄ alkyl, —CH₂C(O)N(H)C₁₋₄alkyl,—C(O)N(H)C₁₋₄alkylOC₁₋₄alkyl, —N(R⁹)C(O)C₁₋₄alky, —CH₂N(R¹³)₂,CH₂N(R⁹)C(O)C₁₋₄alkyl or CH₂N(R¹³)S(O)₂C₁₋₄alkyl. Preferably A isselected from the group consisting optionally substituted pyrazolyl andthiazolyl.

In even more preferred embodiments, A is optionally substituted with 1,2, or 3 groups independently selected from the group consisting of—C₁₋₄alkyl (for example methyl), wherein each —C₁₋₄alkyl is optionallysubstituted by up to 3 halogen, hydroxyl or —OC₁₋₄alkyl groups(preferably one —OC₁₋₄alkyl group; more preferably one —OCH₃ group);—C(O)N(H)C₁₋₄alkyl (for example —C(O)N(H)CH₃) or —C(O)N(R⁹)₂ wherein thetwo R⁹ and the N they are bonded to form a morpholine or pyrrolidinering (preferably a morpholine ring), —CH₂C(O)N(H)C₁₋₄alkyl,—CH₂C(O)N(H)C₁₋₄alkyl, and —C(O)N(H)C₁₋₄alkylOC₁₋₄alkyl; and morepreferably substituted with 1, 2, or 3 groups independently selectedfrom the group consisting of —C₁₋₄alkyl (for example methyl), whereineach —C₁₋₄alkyl is optionally substituted by up to 3 halogen, hydroxylor —OC₁₋₄alkyl groups; —C(O)N(H)C₁₋₄alkyl (for example —C(O)N(H)CH₃) or—C(O)N(R⁹)₂ wherein the two R⁹ and the N they are bonded to form amorpholine or pyrrolidine ring (preferably a morpholine ring),—C(O)N(H)C₁₋₄alkylOC₁₋₄alkyl and CH₂N(R¹³)S(O)₂C₁₋₄alkyl. Preferably Ais selected from the group consisting optionally substituted pyrazolyland thiazolyl.

In one preferred embodiment, A is optionally substituted with 1, 2, or 3groups independently selected from the group consisting of —C₁₋₄alkyl(for example methyl), wherein each —C₁₋₄alkyl is optionally substitutedby up to 3 halogen, hydroxyl or —OC₁₋₄alkyl groups preferably one—OC₁₋₄alkyl group; more preferably one —OCH₃ group); C(O)N(R⁹)₂ (forexample —C(O)N(H)C₁₋₄ alkyl or —C(O)N(R⁹)₂ wherein the two R⁹ groups andthe N they are bonded to form a 4 to 7 membered non-aromaticheterocycle, the heterocycle optionally comprising 1 or 2 furtherheteroatoms selected from N, O and S (for example wherein the two R⁹ andthe N they are bonded to form a morpholine or pyrrolidine ring)),—CH₂C(O)N(R⁹)₂ (for example —CH—₂C(O)N(H)C₁₋₄alkyl), —CH₂C(O)N(R⁹)₂ (forexample —CH₂C(O)N(H)C₁₋₄alkyl), —C(O)N(R¹³)C₁₋₄ alkylOC₁₋₄alkyl (forexample —C(O)N(H)C₁₋₄alkylOC₁₋₄alkyl), —N(R⁹)C(O)C₁₋₄alkyl,CH₂N(R⁹)C(O)C₁₋₄alkyl and CH₂N(R¹³)S(O)₂C₁₋₄alkyl. Preferably A isselected from the group consisting optionally substituted pyrazolyl andthiazolyl.

In one preferred embodiment, A is substituted with 1, 2, or 3 groups,and at least one of the substituents is —C₁₋₄alkyl (for example methyl),wherein each —C₁₋₄alkyl is optionally substituted by up to 3 halogen,hydroxyl or —OC₁₋₄alkyl groups (preferably one —OC₁₋₄alkyl group; morepreferably one —OCH₃ group); C(O)N(R⁹)₂ (for example —C(O)N(H)C₁₋₄alkylor —C(O)N(R⁹)₂ wherein the two R⁹ groups and the N they are bonded toform a 4 to 7 membered non-aromatic heterocycle, the heterocycleoptionally comprising 1 or 2 further heteroatoms selected from N, O andS (for example wherein the two R⁹ and the N they are bonded to form amorpholine or pyrrolidine ring)), —CH₂C(O)N(R⁹)₂ (for example—CH—₂C(O)N(H)C₁₋₄alkyl), —CH₂C(O)N(R⁹)₂ (for example—CH₂C(O)N(H)C₁₋₄alkyl), —C(O)N(R¹³)C₁₋₄alkylOC₁₋₄alkyl (for example—C(O)N(H)C₁₋₄alkylOC₁₋₄alkyl), —N(R⁹)C(O)C₁₋₄alkyl, —CH₂N(R¹³)₂,CH₂N(R⁹)C(O)C₁₋₄alkyl or CH₂N(H)S(O)₂C₁₋₄alkyl. Preferably A is selectedfrom the group consisting optionally substituted pyrazolyl andthiazolyl.

In one preferred embodiment, A is substituted with 1, 2, or 3 groups,and at least one of the substituents is —CH₂N(R¹³)₂ or C₁₋₄alkyl (forexample methyl), wherein each —C₁₋₄alkyl is optionally substituted by upto 3 halogen, hydroxyl or —OC₁₋₄alkyl groups (preferably one —OC₁₋₄alkylgroup; more preferably one —OCH₃ group).

In another preferred embodiment, A is substituted with 1, 2, or 3groups, and at least one of the substituents is C(O)N(R⁹)₂ (for example—C(O)N(H)C₁₋₄alkyl or —C(O)N(R⁹)₂ wherein the two R⁹ groups and the Nthey are bonded to form a 4 to 7 membered non-aromatic heterocycle, theheterocycle optionally comprising 1 or 2 further heteroatoms selectedfrom N, O and S (for example wherein the two R⁹ and the N they arebonded to form a morpholine or pyrrolidine ring)), CH₂N(R⁹)C(O)C₁₋₄alkylor CH₂N(R¹³)S(O)₂C₁₋₄alkyl (for example CH₂N(H)S(O)₂C₁₋₄alkyl).

It has been surprisingly found that where A is substituted with onecarboxamide containing group, stability of the NMT inhibitor isimproved. In one preferred embodiment A is substituted with 1, 2, or 3groups, and at least one of the substituents is —C(O)N(R⁹)₂,—C(O)N(R¹³)C₁₋₄alkylOC₁₋₄alkyl, —C(O)N(C₁₋₄alkylOC₁₋₄alkyl)₂,—CH₂C(O)N(R⁹)₂, —CH—₂C(O)N(R¹³)C₁₋₄alkylOC₁₋₄alkyl,—CH₂C(O)N(C₁₋₄alkylOC₁₋₄alkyl)₂, —NHC(O)C₁₋₄alkyl, —NHC(O)CF₃,CH₂N(R¹³)C(O)C₁₋₄alkyl. In another preferred embodiment, A issubstituted with 1, 2, or 3 groups, and at least one of the substituentsis —C(O)N(R⁹)₂, —C(O)N(R¹³)C₁₋₄alkylOC₁₋₄alkyl,—C(O)N(C₁₋₄alkylOC₁₋₄alkyl)₂, —CH₂C(O)N(R⁹)₂,—CH₂C(O)N(R¹³)C₁₋₄alkylOC₁₋₄alkyl, —CH₂C(O)N(C₁₋₄alkylOC₁₋₄alkyl)₂,—NHC(O)C₁₋₄alkyl, —NHC(O)CF₃, CH₂N(R¹³)C(O)C₁₋₄alkyl, CO₂H, andCH₂N(H)S(O)₂C₁₋₄alkyl.

More preferably, at least one of the substituents is C(O)N(R⁹)₂ (forexample —C(O)N(H)C₁₋₄alkyl or —C(O)N(R⁹)₂ wherein the two R⁹ groups andthe N they are bonded to form a 4 to 7 membered non-aromaticheterocycle, the heterocycle optionally comprising 1 or 2 furtherheteroatoms selected from N, O and S (for example wherein the two R⁹ andthe N they are bonded to form a morpholine or pyrrolidine ring)),—CH₂C(O)N(R⁹)₂ (for example —CH—₂C(O)N(H)C₁₋₄alkyl), —CH₂C(O)N(R⁹)₂ (forexample —CH₂C(O)N(H)C₁₋₄alkyl), —C(O)N(R¹³)C₁₋₄alkylOC₁₋₄alkyl (forexample —C(O)N(H)C₁₋₄alkylOC₁₋₄alkyl), —N(R⁹)C(O)C₁₋₄alkyl,CH₂N(R⁹)C(O)C₁₋₄alkyl or CH₂N(R¹³)S(O)₂C₁₋₄alkyl (for exampleCH₂N(H)S(O)₂C₁₋₄alkyl).

Even more preferably, at least one of the substituents is C(O)N(R⁹)₂(for example —C(O)N(H)C₁₋₄alkyl) or —CH₂C(O)N(R⁹)₂ (for example—CH₂C(O)N(H)C₁₋₄alkyl). In such embodiments, preferably A is substitutedpyrazolyl (such as a 4-pyrazolyl) or thiazolyl (such as a 5-thiazolyl).

In one preferred embodiment, X is O. In another preferred embodiment Xis absent.

In one preferred embodiment, L is —(CH₂)_(m)— or —(CH₂)_(m)O—; morepreferably L is —(CH₂)_(m)—. In one preferred embodiment m is 1 or 2;preferably 2. In one preferred embodiment X is —O—; L is —(CH₂)_(m) andm is 1 or 2.

In one preferred embodiment where, for example, the NMT inhibitor isused as a diagnostic agent for the diagnosis of a disease or disorder inwhich inhibition of NMT provides a therapeutic or prophylactic effect,or as reference compound in a method of discovering other inhibitors ofNMT, L is —(CHR¹²)_(m)— or —(CHR¹²)_(m)O—; and one R¹² is a terminalC₁₋₆alkynyl optionally substituted by up to 3 —F, —Cl, —Br, I, —OH,—OCH₃, —OCF₃ or —CN groups, and more preferably one R¹² is a terminalunsubstituted C₁₋₆alkynyl. Preferably, when present, all other R¹²groups are hydrogen.

In one preferred embodiment R⁷ is hydrogen or methyl, and/or R⁸ ishydrogen or methyl. For the avoidance of doubt, when X is absent and Lis present, R¹ is a group of formula -L-A, in which group L is directlybonded to group A and to the phenyl ring shown in formula (I). When X ispresent and L is absent, R¹ is a group of formula —X-A, in which group Xis directly bonded to group A and to the phenyl ring shown in formula(I). When X and L are both absent, R¹ is a group of formula -A, in whichgroup A is directly bonded to the phenyl ring shown in formula (I).

In one preferred embodiment, X is O, L is —(CH₂)_(m)—, m is 1 or 2, andA is an aromatic carbocycle or heterocycle selected from the groupconsisting of phenyl, pyridinyl, quinolinyl, imidazolyl, benzimidazolyl,pyrazolyl, thiazolyl, 1,2,3-triazolyl and 1,2,4-triazolyl, said aromaticcarbocycle or heterocycle being optionally substituted with 1, 2, or 3groups independently selected from the group consisting of —C₁₋₄alkyl(for example methyl), wherein each —C₁₋₄alkyl is optionally substitutedby up to 3 halogen, hydroxyl or —OC₁₋₄alkyl groups; —C(O)N(R⁹)₂ (forexample —C(O)N(H)C₁₋₄alkyl); and —CH₂C(O)N(R⁹)₂ (for example—CH—₂C(O)N(H)C₁₋₄alkyl). More preferably A is selected from the groupconsisting optionally substituted pyrazolyl and thiazolyl.

In one preferred embodiment, X is absent, L is —(CH₂)_(m)—, m is 3, andA is an aromatic carbocycle or heterocycle selected from the groupconsisting of phenyl, pyridinyl, quinolinyl, imidazolyl, benzimidazolyl,pyrazolyl, thiazolyl, 1,2,3-triazolyl and 1,2,4-triazolyl, said aromaticcarbocycle or heterocycle being optionally substituted with 1, 2, or 3groups independently selected from the group consisting of —C₁₋₄alkyl(for example methyl), wherein each —C₁₋₄alkyl is optionally substitutedby up to 3 halogen, hydroxyl or —OC₁₋₄alkyl groups; —C(O)N(R⁹)₂ (forexample —C(O)N(H)C₁₋₄alkyl); and —CH₂C(O)N(R⁹)₂ (for example—CH—₂C(O)N(H)C₁₋₄alkyl). Preferably A is selected from the groupconsisting optionally substituted pyrazolyl and thiazolyl.

In one preferred embodiment, R³ and R⁴ are both hydrogen. In anotherpreferred embodiment, R³ is hydrogen and R⁴ is methyl.

In one preferred embodiment, R⁵ and R⁶ are both methyl. In anotherpreferred embodiment, R⁵ and R⁶ are both hydrogen. In another preferredembodiment, R⁵ is hydrogen and R⁶ is methyl.

In another embodiment, q is 0 or 1 and the R³ group and the R⁵ group andthe intervening atoms form a 3 to 7 membered non-aromatic heterocyclecomposed of the intervening atoms and bond, or the intervening atoms and—(CHR^(a))r. Preferably a 4 to 6 membered non-aromatic heterocycle isformed; and more preferably a 4 membered non-aromatic heterocycle. Inembodiments where a 4 membered non-aromatic heterocycle is formed,preferably q is 1.

In another embodiment, q is 1 and the R¹⁰ group and the R⁵ group and theintervening atoms form a 3 to 7 membered non-aromatic heterocyclecomposed of the intervening atoms and —(CHR^(a))_(r)—. Preferably a 4 to6 membered non-aromatic heterocycle is formed.

It has been surprisingly found that stability, and in particulart_(1/2), of the NMT inhibitors according to the invention can beimproved when q is 1, and when q is land the R³ group and the R⁵ groupand the intervening atoms form a non-aromatic heterocycle composed ofthe intervening atoms and —(CHR^(a))_(r)—, for example when a 4 memberedring is formed wherein r is 1. Therefore, in one preferred embodiment qis 1 and the R³ group and the R⁵ group and the intervening atoms form a4 membered non-aromatic heterocycle composed of the intervening atomsand —(CHR^(a))_(r), wherein r is 1.

It has also been surprisingly found that rapid metabolism can beachieved when q is 0. Compounds having a short t_(1/2) can beadvantageous to reduce side effects and/or for administration methods inwhich rapid metabolism is advantageous, for example delivery byinhalation. Therefore, in another preferred embodiment q is 0.

In one preferred embodiment, A is phenyl, X is —O—; L is —(CH₂)_(m)—; mis 1 or 2; s is 0; E, J and G are each C(R⁷); K is carbon; Q is N(R⁸); Mis nitrogen; R³ and R⁴ are each hydrogen; R⁵ and R⁶ are each methyl; andR⁵ is hydrogen.

In one preferred embodiment, A is 3-pyridinyl. In one preferredembodiment, the compound has the formula (IA′) or (IB′)

wherein R¹ is a group of formula —X-L-A; A is 3-pyridinyl; X is —O—; Lis —(CH₂)_(m)—; m is 1 or 2; R^(2′) is hydrogen or fluorine; Q is N(R⁸);M is nitrogen; E, J and G are each C(R⁷); K is carbon; R³ and R⁴ areeach hydrogen; R⁵ and R⁶ are each methyl; and R⁸ is hydrogen.

In one preferred embodiment, A is 4-quinolinyl. In one preferredembodiment, A is 4-quinolinyl; X is —O—; L is —(CH₂)_(m)—; m is 1 or 2;s is 0; E, J and G are each C(R⁷); K is carbon; Q is N(R⁸); M isnitrogen; R³ and R⁴ are each hydrogen; R⁵ and R⁶ are each methyl; and R⁸is hydrogen.

In one preferred embodiment, A is 1-imidazolyl, said imidazolyl beingoptionally substituted by 1 or 2 methyl groups. In one preferredembodiment, the compound has the formula (IA′) or (IB′)

wherein R¹ is a group of formula —X-L-A; A is 1-imidazolyl, saidimidazolyl being optionally substituted by 1 or 2 methyl groups; X is—O—; L is —(CH₂)_(m)—; m is 1 or 2; R^(2′) is hydrogen or fluorine; E, Jand G are each C(R⁷); K is carbon; Q is N(R⁸); M is nitrogen; R³ and R⁴are each hydrogen; R⁵ and R⁶ are each methyl; and R⁸ is hydrogen ormethyl.

In one preferred embodiment, A is 1-benzimidazolyl. In one preferredembodiment, the compound has the formula (IA′)

wherein R¹ is a group of formula —X-L-A; A is 1-benzimidazolyl; X is—O—; L is —(CH₂)_(m)—; m is 1 or 2; R^(2′) is fluorine or hydrogen; E, Jand G are each C(R⁷); K is carbon; Q is N(R⁸); M is nitrogen; R³ and R⁴are each hydrogen; R⁵ and R⁶ are each methyl; and R⁸ is hydrogen.

In one preferred embodiment, A is an optionally substituted 4-pyrazolyl,such as a 4-pyrazolyl optionally substituted by up to 3 substituentsindependently selected from the group consisting of —C₁₋₄alkyl, whereineach —C₁₋₄alkyl is optionally substituted by up to 3 halogen, hydroxylor —OC₁₋₄alkyl groups; —C(O)N(R⁹)₂ (for example —C(O)N(H)C₁₋₄alkyl), and—CH₂C(O)N(R⁹)₂ (for example —CH₂C(O)N(H)C₁₋₄alkyl); and R⁹ where presentis each selected from the group consisting of hydrogen and —C₁₋₄alkyl,or two R⁹ groups and the N they are bonded to from a 4 to 7 memberednon-aromatic heterocycle, the heterocycle optionally comprising 1 or 2further heteroatoms selected from N, O and S. Preferably A is4-pyrazolyl optionally substituted by up to 3 —C₁₋₄alkyl;—CH₂OC₁₋₄alkyl, CF₂H, CF₃, C(O)N(Me)₂, —C(O)-1-pyrazole; or—C(O)-4-morpholine groups. More preferably A is 4-pyrazolyl substitutedwith one or two methyl groups and one —C₁₋₄alkyl; —CH₂OC₁₋₄alkyl, CF₂H,CF₃, C(O)N(Me)₂, —C(O)-1-pyrazole; or —C(O)-4-morpholine group.

In one preferred embodiment, the compound has the formula (IA″)

(for example

wherein R¹ is a group of formula —X-L-A; A is 4-pyrazolyl, saidpyrazolyl being optionally substituted with up to 3 methyl groups; X is—O— or absent (preferably —O—); L is —(CH₂)_(m)— or —(CH₂)_(m)—O—(preferably —(CH₂)_(m)—); m is 1, 2 or 3 (preferably 1 or 2); eachR^(2′) is independently selected from the group consisting of hydrogen,fluorine, chlorine, —CN and methyl; R³ and R⁴ are each hydrogen; R³ ishydrogen or methyl; R⁴ is hydrogen or methyl; R⁵ is hydrogen or methyl;R⁶ is hydrogen or methyl;

when present R¹⁰ is hydrogen or methyl;

when present R¹¹ is hydrogen or methyl;

or the R³ group and the R⁵ group and the intervening atoms form a 3 to 7membered non-aromatic heterocycle composed of the intervening atoms andbond, or the intervening atoms and —(CHR^(a))_(r)—; or the R¹⁰ group andthe R⁵ group and the intervening atoms form a 3 to 7 memberednon-aromatic heterocycle composed of the intervening atoms and—(CHR^(a))_(r)—; (more preferably at least one of R⁵ and R⁶ is methyl,most preferably R⁵ and R⁶ are both methyl);

r is 1, 2, 3, 4 or 5; R^(a) is hydrogen or methyl;

R⁷ where present is hydrogen or methyl; R⁸ where present is hydrogen ormethyl; and E, J, G, K, Q and M are as defined in formula (I). Withinthat embodiment, preferably

i) E, J and G are each C(R⁷), K is carbon, Q is N(R⁸), M is nitrogen;and R⁸ is hydrogen or methyl;

ii) E, J and G are each C(R⁷), and K, Q and M are each nitrogen;

iii) E and G are each C(R⁷), and J, K, Q and M are each nitrogen;

iv) J and G are each C(R⁷), and E, K, Q and M are each nitrogen; or

v) E, J, G and M are each C(R⁷), and K and Q are each nitrogen; and morepreferably E, J and G are each C(R⁷), and K, Q and M are each nitrogen;E, J and G are each C(R⁷), K is carbon, Q is N(R⁸), M is nitrogen, andR^(a) is hydrogen or methyl; or E, J, G and M are each C(R⁷), and K andQ are each nitrogen.

Also within that embodiment, preferably, Y is —CH— or —C(R^(2′))—.

Also within that embodiment, the compound may have formula(IA{circumflex over ( )}{circumflex over ( )}{circumflex over ( )})

and wherein R^(2′) is selected from the group consisting of fluorine,chlorine, —CN and methyl (preferably fluorine); and

R^(2″) is selected from the group consisting of hydrogen, fluorine,chlorine, —CN and methyl; or the compound may have formula(IA{circumflex over ( )}{circumflex over ( )})

wherein R^(2′) is selected from the group consisting of fluorine,chlorine, —CN and methyl (preferably fluorine); and

R^(2″) is selected from the group consisting of hydrogen, fluorine,chlorine, —CN and methyl; or the compound may have formula(IA{circumflex over ( )}{circumflex over ( )}{circumflex over ( )})

wherein R^(2′) is selected from the group consisting of fluorine,chlorine, —CN and methyl (preferably fluorine); and

R^(2″) is selected from the group consisting of hydrogen, fluorine,chlorine, —CN and methyl.

In certain embodiments within the above-mentioned embodiment, R¹ is agroup of formula —X-L-A; A is 4-pyrazolyl, said pyrazolyl beingoptionally substituted with up to 3 methyl groups; X is —O— or absent; Lis —(CH₂)_(m)— or —(CH₂)_(m)—O—; m is 2; R^(2′) is selected from thegroup consisting of fluorine, chlorine —CN and methyl (preferablyfluorine); q is 0,

R³ is hydrogen or methyl; R⁴ is hydrogen or methyl;

R⁵ is hydrogen or methyl; R⁶ is hydrogen or methyl; or the R³ group andthe R⁵ group and the intervening atoms form a 3 to 7 memberednon-aromatic heterocycle composed of the intervening atoms and bond, orthe intervening atoms and —(CHR^(a))_(r)—; (more preferably R⁵ and R⁶are both methyl); R⁷ where present is hydrogen or methyl; R^(a) wherepresent is hydrogen or methyl; and E, J, G, K, Q and M are as defined informula (I); and, preferably

i) E, J and G are each C(R⁷), K is carbon, Q is N(R⁸), M is nitrogen;and R⁸ is hydrogen or methyl;

ii) E, J and G are each C(R⁷), and K, Q and M are each nitrogen;

iii) E and G are each C(R⁷), and J, K, Q and M are each nitrogen;

iv) J and G are each C(R⁷), and E, K, Q and M are each nitrogen; or

v) E, J, G and M are each C(R⁷), and K and Q are each nitrogen.

In certain embodiments of the above-mentioned embodiment, R¹ is a groupof formula —X-L-A; A is 4-pyrazolyl, said pyrazolyl being optionallysubstituted with up to 3 methyl groups; X is —O— or absent; L is—(CH₂)_(m)— or —(CH₂)_(m)—O—; m is 2; R^(2′) is fluorine; R³ and R⁴ areeach hydrogen; q is 0, R⁵ and R⁶ are each independently hydrogen ormethyl (more preferably R⁵ and R⁶ are both methyl); or the R³ group andthe R⁵ group and the intervening atoms form a 3 to 7 memberednon-aromatic heterocycle composed of the intervening atoms and bond, orthe intervening atoms and —(CHR^(a))_(r)—; R⁷ where present is hydrogenor methyl; R⁸ is methyl; K is carbon; Q is N(R⁸); M is nitrogen; and E,J and G are as defined in formula (I); or

R¹ is a group of formula —X-L-A; A is 4-pyrazolyl, said pyrazolyl beingoptionally substituted with up to 3 methyl groups; X is —O— or absent; Lis —(CH₂)_(m)— or —(CH₂)_(m)—O—; m is 2; R² is fluorine; R³ and R⁴ areeach hydrogen; R⁵ and R⁶ are each independently hydrogen or methyl (morepreferably R⁵ and R⁶ are both methyl); R⁷ where present is hydrogen ormethyl; Q, M and K are each nitrogen; and E, J and G are each C(R⁷).

In one preferred embodiment, the compound has the formula (IA′)

wherein R¹ is a group of formula —X-L-A; A is 4-pyrazolyl, saidpyrazolyl being optionally substituted with up to 3 methyl groups; X is—O— or absent; L is —(CH₂)_(m)— or —(CH₂)_(m)—O—; m is 2; R^(2′) isselected from the group consisting of fluorine, chlorine —CN and methyl(preferably fluorine);

R³ is hydrogen or methyl; R⁴ is hydrogen or methyl;

R⁵ is hydrogen or methyl; R³ is hydrogen or methyl; or

the R³ group and the R⁵ group and the intervening atoms form a 3 to 7membered non-aromatic heterocycle composed of the intervening atoms andbond, or the intervening atoms and —(CHR^(a))_(r)—; (more preferably R⁵and R⁶ are both methyl); R⁷ where present is hydrogen or methyl; R⁸where present is hydrogen or methyl; and E, J, G, K, Q and M are asdefined in formula (I). Within that embodiment, preferably

i) E, J and G are each C(R′), K is carbon, Q is N(R⁸), M is nitrogen;and R¹ is hydrogen or methyl;

ii) E, J and G are each C(R⁷), and K, Q and M are each nitrogen;

iii) E and G are each C(R⁷), and J, K, Q and M are each nitrogen;

iv) J and G are each C(R⁷), and E, K, Q and M are each nitrogen; or

v) E, J, G and M are each C(R⁷), and K and Q are each nitrogen.

In one preferred embodiment, the compound has the formula (IA′)

wherein R¹ is a group of formula —X-L-A; A is 4-pyrazolyl, saidpyrazolyl being optionally substituted with up to 3 methyl groups; X is—O— or absent; L is —(CH₂)_(m)— or —(CH₂)_(m)—O—; m is 2; R² isfluorine; R³ and R⁴ are each hydrogen; R⁵ and R⁶ are each independentlyhydrogen or methyl (more preferably R⁵ and R⁶ are both methyl); R⁷ wherepresent is hydrogen or methyl; R⁸ is methyl; K is carbon; Q is N(R⁸); Mis nitrogen; and E, J and G are as defined in formula (I).

In one preferred embodiment, the compound has the formula (IA′)

wherein R¹ is a group of formula —X-L-A; A is 4-pyrazolyl, saidpyrazolyl being optionally substituted with up to 3 methyl groups; X is—O— or absent; L is —(CH₂)_(m)— or —(CH₂)_(m)—O—; m is 2; R^(2′) isfluorine; R³ and R⁴ are each hydrogen; R⁵ and R⁶ are each independentlyhydrogen or methyl (more preferably R⁵ and R⁶ are both methyl); R⁷ wherepresent is hydrogen or methyl; Q, M and K are each nitrogen; and E, Jand G are each C(R⁷).

In one preferred embodiment, the compound has the formula (IA″″)

wherein R¹ is a group of formula —X-L-A; A is 4-pyrazolyl, saidpyrazolyl being optionally substituted with up to 3 methyl groups; X is—O— or absent; L is —(CH₂)_(m)— or —(CH₂)_(m)—O—; m is 2; R^(2′) isselected from the group consisting of fluorine, —CN and methyl; R³ andR⁴ are each hydrogen; R⁵ and R⁶ are each independently hydrogen ormethyl (more preferably R⁵ and R⁶ are both methyl); R⁷ where present ishydrogen or methyl; R⁸ where present is hydrogen or methyl; and E, J, G,K, Q and M are as defined in formula (I). Within that embodiment,preferably

i) E, J and G are each C(R⁷), K is carbon, Q is N(R⁸), M is nitrogen;and R^(e) is hydrogen or methyl;

ii) E, J and G are each C(R⁷), and K, Q and M are each nitrogen;

iii) E and G are each C(R⁷), and J, K, Q and M are each nitrogen;

iv) J and G are each C(R⁷), and E, K, Q and M are each nitrogen; or

v) E, J, G and M are each C(R⁷), and K and Q are each nitrogen.

In one preferred embodiment, the compound has the formula (IA″″)

wherein R¹ is a group of formula —X-L-A; A is 4-pyrazolyl, saidpyrazolyl being optionally substituted with up to 3 methyl groups; X is—O— or absent; L is —(CH₂)_(m)— or —(CH₂)_(m)—O—; m is 2; R^(2′) isfluorine; R³ and R⁴ are each hydrogen; R⁵ and R⁶ are each independentlyhydrogen or methyl (more preferably R⁵ and R⁶ are both methyl); R⁷ wherepresent is hydrogen or methyl; R⁸ is methyl; K is carbon; Q is N(R⁸); Mis nitrogen; and E, J and G are as defined in formula (I).

In one preferred embodiment, the compound has the formula (IA″″)

wherein R¹ is a group of formula —X-L-A; A is 4-pyrazolyl, saidpyrazolyl being optionally substituted with up to 3 methyl groups; X is—O— or absent; L is —(CH₂)_(m)— or —(CH₂)_(m)—O—; m is 2; R^(2′) isfluorine; R³ and R⁴ are each hydrogen; R⁵ and R⁶ are each independentlyhydrogen or methyl (more preferably R⁵ and R⁶ are both methyl); R⁷ wherepresent is hydrogen or methyl; Q, M and K are each nitrogen; and E, Jand G are each C(R⁷).

In one preferred embodiment, A is an optionally substituted 5-thiazolyl,such as a 5-thiazolyl optionally substituted by 1 or 2 methyl groups. Inone preferred embodiment, the compound has the formula (IA″)

-   -   (for example

wherein R¹ is a group of formula —X-L-A; A is 5-thiazolyl optionallysubstituted with 1 or 2 methyl groups (more preferably A is 5-thiazolylsubstituted with one methyl group at the 4-position; or substituted withtwo methyl groups, one at the 2-position and one at the 4-position); Xis —O—; L is —(CH₂)_(m)—; m is 1, 2 or 3 (preferably 1 or 2); R^(2′) ishydrogen, chlorine or fluorine (preferably fluorine); R³ is hydrogen ormethyl; R⁴ is hydrogen or methyl;

R⁵ is hydrogen or methyl; R⁵ is hydrogen or methyl;

when present R¹⁰ is hydrogen or methyl;

when present R¹¹ is hydrogen or methyl;

or the R³ group and the R⁵ group and the intervening atoms form a 3 to 7membered non-aromatic heterocycle composed of the intervening atoms andbond, or the intervening atoms and —(CHR^(a))_(r)—; or the R¹⁰ group andthe R⁵ group and the intervening atoms form a 3 to 7 memberednon-aromatic heterocycle composed of the intervening atoms and—(CHR^(a))_(r)—;

r is 1, 2, 3, 4 or 5; R^(a) is hydrogen or methyl (preferably R³ and R⁴are each independently hydrogen or methyl; and R⁵ and R⁶ are eachindependently hydrogen or methyl;) K is carbon; Q is N(R⁸); M isnitrogen; R⁸ is methyl; and E, J and G are as defined in formula (I).

Also within that embodiment, preferably, Y is —CH— or —C(R^(2′))—.

Also within that embodiment, the compound may have formula(IA{circumflex over ( )})

and wherein R^(2′) is selected from the group consisting of fluorine andchlorine (preferably fluorine); and

R^(2′) is selected from the group consisting of hydrogen, fluorine andchlorine; or the compound may have formula (IA{circumflex over( )}{circumflex over ( )})

wherein R^(2′) is selected from the group consisting of fluorine andchlorine (preferably fluorine); and

R^(2″) is selected from the group consisting of hydrogen, fluorine andchlorine; or the compound may have formula (IA{circumflex over( )}{circumflex over ( )}{circumflex over ( )})

wherein R^(2′) is selected from the group consisting of fluorine andchlorine (preferably fluorine); and

R^(2″) is selected from the group consisting of hydrogen, fluorine andchlorine.

In one preferred embodiment, the compound has the formula (IA′)

wherein R¹ is a group of formula —X-L-A; A is 5-thiazolyl optionallysubstituted with 1 or 2 methyl groups (more preferably A is 5-thiazolylsubstituted with one methyl group at the 4-position; or substituted withtwo methyl groups, one at the 2-position and one at the 4-position); Xis —O—; L is —(CH₂)_(m)—; m is 1, 2 or 3 (preferably 3); R^(2′) ishydrogen, chlorine or fluorine (preferably fluorine); R³ is hydrogen ormethyl; R⁴ is hydrogen or methyl;

R⁵ is hydrogen or methyl; R⁵ is hydrogen or methyl;

when present R¹⁰ is hydrogen or methyl;

when present R¹¹ is hydrogen or methyl;

or the R³ group and the R⁵ group and the intervening atoms form a 3 to 7membered non-aromatic heterocycle composed of the intervening atoms andbond, or the intervening atoms and —(CHR^(a))_(r)—; or the R¹⁰ group andthe R⁵ group and the intervening atoms form a 3 to 7 memberednon-aromatic heterocycle composed of the intervening atoms and—(CHR^(a))_(r)—;

r is 1, 2, 3, 4 or 5; R^(a) is hydrogen or methyl (preferably R³ and R⁴are each independently hydrogen or methyl; and R⁵ and R⁶ are eachindependently hydrogen or methyl); K, Q and M are each nitrogen; and E,J and G are as defined in formula (I).

In one preferred embodiment, A is selected from the group consisting ofoptionally substituted 1,2,4-triazol-1-yl, optionally substituted1,2,4-triazol-4-yl, optionally substituted 1,2,4-triazol-3-yl andoptionally substituted 1,2,3-triazol-4-yl. Within that embodiment,preferably X is absent and L is —(CH₂)₃—. A is preferably optionallysubstituted 1,2,4-triazol-1-yl.

In one preferred embodiment, the compound has the formula (IA′″)

wherein R¹ is a group of formula —X-L-A; A is selected from the groupconsisting of optionally substituted 1,2,4-triazol-1-yl, optionallysubstituted 1,2,4-triazol-4-yl, optionally substituted1,2,4-triazol-3-yl and optionally substituted 1,2,3-triazol-4-yl; X is—O— or absent; L is —(CH₂)_(m)—; m is 2 or 3; R^(2′) is hydrogen orfluorine (more preferably R^(2′) is fluorine); R^(2″) is hydrogen or—OCH₃; R³ and R⁴ are each hydrogen; R⁵ and R⁶ are each methyl; K iscarbon; Q is N(R⁸); M is nitrogen; R⁸ is methyl or hydrogen; and E, Jand G are as defined in formula (I). Within that embodiment, preferablyX is absent and L is —(CH₂)₃—.

In one preferred embodiment, the compound has the formula (IA′″)

wherein R¹ is a group of formula —X-L-A; A is selected from the groupconsisting of optionally substituted 1,2,4-triazol-1-yl, optionallysubstituted 1,2,4-triazol-4-yl, optionally substituted1,2,4-triazol-3-yl and optionally substituted 1,2,3-triazol-4-yl; X is—O— or absent; L is —(CH₂)_(m)—; m is 2 or 3; R^(2′) is hydrogen orfluorine (more preferably R^(2′) is fluorine); R^(2″) is hydrogen or—OCH₃; R³ and R⁴ are each hydrogen; R⁵ and R⁶ are each methyl; K, Q andM are each nitrogen; and E, J and G are as defined in formula (I).Within that embodiment, preferably X is absent and L is —(CH₂)₃—.

In one preferred embodiment, the compound has the formula (IA′″)

wherein R¹ is a group of formula —X-L-A; A is selected from the groupconsisting of optionally substituted 1,2,4-triazol-1-yl, optionallysubstituted 1,2,4-triazol-4-yl, optionally substituted1,2,4-triazol-3-yl and optionally substituted 1,2,3-triazol-4-yl; X isabsent; L is —(CH₂)₃—; R^(2′) is fluorine; R^(2″) is hydrogen or —OCH₃;R³ and R⁴ are each hydrogen; R⁵ and R⁶ are each methyl; K, Q and M areeach nitrogen; and E, J and G are as defined in formula (I).

In one embodiment, the compound has the formula (IB)

wherein R¹ is a group of formula —X-L-A; X is —O—; L is —(CH₂)_(m)—; mis 1 or 2; A is selected from the group consisting of optionallysubstituted 3-pyridinyl, 4-pyridinyl and 1-imidazolyl;

s is 0; R³ and R⁴ are each hydrogen; R⁵ and R⁶ are each methyl; K iscarbon; Q is N(R⁸); M is nitrogen; and R⁸ is hydrogen; and E, J, and Gare as defined in formula (I).

In one embodiment, the compound has the formula (IB)

-   -   (for example

wherein R¹ is a group of formula —X-L-A; X is —O—; L is —(CH₂)_(m)—; mis 1 or 2;

A is selected from the group consisting of optionally substituted3-pyridinyl, 4-pyridinyl and 1-imidazolyl;

s is 0 or 1; R² is fluorine; q is 0 or 1 (preferably q is 0); R³ and R⁴are each hydrogen; R⁵ and R⁶ are each methyl; R¹⁰ and R¹¹ are eachhydrogen or methyl; K, Q and M are each nitrogen; and E, J, and G are asdefined in formula (I).

NMT inhibitors of the invention include, but are not limited to, thecompounds specifically named in the Examples herein, and salts thereof.In one embodiment, the NMT inhibitor is any one of Example compound nos.1 to 122 (for example, Example compound nos. 1 to 108, 1 to 101, 1 to67, or 1 to 51), or a salt thereof. In one embodiment, the NMT inhibitoris a compound selected from the group consisting of: 17, 7, 18, 30, 29,24, 36, 35, 33, 37, 45, 46, 47, 48, 49, and 50, or a salt thereof.

In one preferred embodiment, the NMT inhibitor compound of the inventionis selection from the groups consisting of example 2, 3, 4, 6, 7, 8, 9,10, 11, 12, 13, 17, 18, 19, 20, 22, 23, 24, 26, 28, 29, 30 and 32, 33,34, 35, 36, 37, 38, 39, 41, 42, 43, 45, 46, 48, 49, and 50, 53, 55, 56,57, 58, 60, 62, 63, 66, 67, 68, 69, 70, 71, 72, 74, 75, 76, 77, 78, 79,80, 81, 82, 86, 86, 88, 89, 90, 91, 92, 93, 94, 95, and 96. In anotherpreferred embodiment, the compound of the invention is selection fromthe groups consisting of example 8, 9, 17, 18, 20, 22, 24, 29, 30, 31,32, 33, 35, 36, 39, and 48. In another preferred embodiment, thecompound of the invention is selection from the groups consisting ofexample 7 and 8. In another preferred embodiment, the compound of theinvention is selection from the groups consisting of example 7, 8, 17and 18.

In another preferred embodiment, the compound of the invention isselection from the groups consisting of example 7, 17, 53, 56, 70, 77,78, 85, 92, 94. In another preferred embodiment, the compound of theinvention is selection from the groups consisting of example 8, 17.18,29, 30, 35, 37, 39, 53, 55, 56, 62, 68, 70, 72, 76 and 92. In anotherpreferred embodiment, the compound of the invention is selection fromthe groups consisting of example 7, 17, 18 and 30. In another preferredembodiment, the compound of the invention is selection from the groupsconsisting of example 17, 18, 30, 49, 50, 62, 63, 70, 76, 77, 83, 86,94, 97, and 100. In another preferred embodiment, the compound of theinvention is selection from the groups consisting pf example 30, 34, 49,and 50.

In one embodiment, the NMT inhibitor is any one of the followingcompounds:

or a salt thereof. In another embodiment, the NMT inhibitor is any oneof the following compounds:

or a salt thereof.

As mentioned above, the compounds of the invention have activity asinhibitors of N-myristoyl transferase. The NMT inhibitors of theinvention may be competitive inhibitors or partial competitiveinhibitors of the NMT enzyme. The NMT inhibitors of the invention maythus be used in the treatment of diseases or disorders associated withNMT activity or may be used in the treatment of a disease or disorder bytargeting NMT activity (for example in microbial infections,hyperproliferative diseases, picornavirus infections). Accordingly,there is provided an NMT inhibitor according to the invention, or apharmaceutical composition comprising the NMT inhibitor and apharmaceutically acceptable carrier, for use as a medicament. There isalso provided an NMT inhibitor according to the invention, or apharmaceutical composition comprising the NMT inhibitor and apharmaceutically acceptable carrier, for use in the treatment orprophylaxis of a disease or disorder in which inhibition of N-myristoyltransferase provides a therapeutic or prophylactic effect.

The invention also provides a method for the treatment or prophylaxis ofa disease or disorder in a subject in which inhibition of N-myristoyltransferase provides a therapeutic or prophylactic effect in a mammal,which comprises administering to the mammal a therapeutically effectiveamount of an NMT inhibitor according to the invention, or of apharmaceutical composition comprising the NMT inhibitor and apharmaceutically acceptable carrier.

The invention also provides the use of an NMT inhibitor according to theinvention for the manufacture of a medicament for the treatment orprophylaxis of a disease or disorder in which inhibition of N-myristoyltransferase provides a therapeutic or prophylactic effect.

Diseases or disorders in which inhibition of N-myristoyl transferaseprovides a therapeutic or prophylactic effect include microbialinfections; e.g. fungal infections, and protozoan infections such asmalaria, leishmaniasis, human African trypanosomiasis (sleepingsickness) and American trypanosomiasis (Chagas disease).

In one preferred embodiment, the disease or disorder is a protozoaninfection caused by a species of Plasmodium, Leishmania or Trypanosoma(for example Plasmodium falciparum, Plasmodium vivax, Leishmaniadonovani, Leishmania major, Trypanosoma brucei, Trypanosoma cruzi).

As mentioned above, inhibition of human NMT has also been suggested as atarget for treating or preventing various diseases or disorders, forexample hyperproliferative disorders (cancers, e.g. human colorectalcancer, gallbladder carcinoma, brain tumors, lymphomas such as B-celllymphoma), and viral infections such as picornavirus infections, forexample rhinovirus (HRV, also known as the common cold) or lentivirusinfections for example HIV, and so NMT inhibitors of the invention finduse the treatment or prevention of those disorders.

Further diseases or disorders in which inhibition of N-myristoyltransferase provides a therapeutic or prophylactic effect includeneurological diseases/disorders, ischemia, osteoporosis and diabetes.

Compounds of the invention which are selective for the NMT enzyme of aparticular species (e.g. Plasmodium falciparum, Plasmodium vivax,Leishmania donovani, Leishmania major, Trypanosoma brucei, Trypanosomacruzi) over human NMT (human NMT1 and/or human NMT2) may be particularlyuseful in the treatment of conditions associated with those species(e.g. malaria, leishmaniasis, sleeping sickness). For example, use of aselective NMT inhibitor may result in fewer side effects compared withuse of a less selective compound. In one preferred embodiment, NMTinhibitors are selective for a non-human NMT (e.g. Plasmodiumfalciparum, Plasmodium vivax, Leishmania donovani, Trypanosoma bruceiand/or Trypanosoma cruzi) over human NMT (e.g. over human NMT1 and/orhuman NMT2). NMT inhibitors are considered selective if the ratio ofhuman NMT IC₅₀ value to non-human NMT IC₅₀ value is greater than 5,preferably greater than 10, more preferably greater than 100, mostpreferably greater than 1000.

Compounds which are particularly good inhibitors of human NMT may bepreferred for use in the treatment and/or prevention of viral infections(e.g. HIV, HRV) and cancers, as well as other conditions for whichinhibition of human NMT has been suggested as a means of therapy.

The NMT inhibitor of the invention may be in the form of apharmaceutically acceptable salt. Salts of compounds of the inventionwhich are suitable for use in medicine are those wherein a counter-ionis pharmaceutically acceptable. However, salts havingnon-pharmaceutically acceptable counter-ions are within the scope of thepresent invention, for example, for use as intermediates in thepreparation of the compounds of the invention and their pharmaceuticallyacceptable salts.

Suitable salts according to the invention include those formed withorganic or inorganic acids or bases. In particular, suitable saltsformed with acids according to the invention include those formed withmineral acids, strong organic carboxylic acids, such as alkanecarboxylicacids of 1 to 4 carbon atoms which are unsubstituted or substituted, forexample, by halogen, such as saturated or unsaturated dicarboxylicacids, such as hydroxycarboxylic acids, such as amino acids, or withorganic sulfonic acids, such as (C₁-C₄)-alkyl- or aryl-sulfonic acidswhich are unsubstituted or substituted, for example by halogen.Pharmaceutically acceptable acid addition salts include those formedfrom hydrochloric, hydrobromic, sulphuric, nitric, citric, tartaric,acetic, phosphoric, lactic, pyruvic, acetic, trifluoroacetic, succinic,perchloric, fumaric, maleic, glycolic, lactic, salicylic, oxaloacetic,methanesulfonic, ethanesulfonic, p-toluenesulfonic, formic, benzoic,malonic, naphthalene-2-sulfonic, benzenesulfonic, isethionic, ascorbic,malic, phthalic, aspartic, and glutamic acids, lysine and arginine.Other acids, which may or may not in themselves be pharmaceuticallyacceptable, may be useful as intermediates in obtaining the compounds ofthe invention and their pharmaceutical acceptable acid addition salts.

Pharmaceutically acceptable base salts include ammonium salts, alkalimetal salts, for example those of potassium and sodium, alkaline earthmetal salts, for example those of calcium and magnesium, and salts withorganic bases, for example dicyclohexylamine, N-methyl-D-glucomine,morpholine, thiomorpholine, piperidine, pyrrolidine, a mono-, di- ortri-lower alkylamine, for example ethyl-, tert-butyl-, diethyl-,diisopropyl-, triethyl-, tributyl- or dimethyl-propylamine, or a mono-,di- or trihydroxy lower alkylamine, for example mono-, di- ortriethanolamine. Corresponding internal salts may furthermore be formed.

Those skilled in the art of organic chemistry will appreciate that manyorganic compounds can form complexes with solvents in which they arereacted or from which they are precipitated or crystallized. Thesecomplexes are known as “solvates”. For example, a complex with water isknown as a “hydrate”. Solvates, such as hydrates, exist when the drugsubstance incorporates solvent, such as water, in the crystal lattice ineither stoichiometric or non-stoichiometric amounts. Drug substances areroutinely screened for the existence of hydrates since these may beencountered at any stage of the drug manufacturing process or uponstorage of the drug substance or dosage form. Solvates are described inS. Byrn et al., Pharmaceutical Research, 1995. 12 (7): p. 954-954, andWater-Insoluble Drug Formulation, 2^(nd) ed. R. Liu, CRC Press, page553, which are incorporated herein by reference. Accordingly, it will beunderstood by the skilled person that the NMT inhibitors of theinvention may therefore be present in the form of solvates. Solvates ofNMT inhibitors of the invention which are suitable for use in medicineare those wherein the associated solvent is pharmaceutically acceptable.For example, a hydrate is an example of a pharmaceutically acceptablesolvate. However, solvates having non-pharmaceutically acceptableassociated solvents may find use as intermediates in the preparation ofthe NMT inhibitors according to the invention.

The amount of active ingredient which is required to achieve atherapeutic effect will, of course, vary with the particular compound,the route of administration, the subject under treatment, including thetype, species, age, weight, sex, and medical condition of the subjectand the renal and hepatic function of the subject, and the particulardisorder or disease being treated, as well as its severity. Anordinarily skilled physician, veterinarian or clinician can readilydetermine and prescribe the effective amount of the drug required toprevent, counter or arrest the progress of the condition.

Oral dosages of the present invention, when used for the indicatedeffects, will range between about 0.01 mg per kg of body weight per day(mg/kg/day) to about 100 mg/kg/day, preferably 0.01 mg per kg of bodyweight per day (mg/kg/day) to 10 mg/kg/day, and most preferably 0.1 to5.0 mg/kg/day, for adult humans. For oral administration, thecompositions are preferably provided in the form of tablets or otherforms of presentation provided in discrete units containing 0.01, 0.05,0.1, 0.5, 1.0, 2.5, 5.0, 10.0, 15.0, 25.0, 50.0, 100, and 500 milligramsof the active ingredient for the symptomatic adjustment of the dosage tothe patient to be treated. A medicament typically contains from about0.01 mg to about 500 mg of the active ingredient, preferably from about1 mg to about 100 mg of active ingredient. Intravenously, the mostpreferred doses will range from about 0.1 to about 10 mg/kg/minuteduring a constant rate infusion. Advantageously, NMT inhibitors of thepresent invention may be administered in a single daily dose, or thetotal daily dosage may be administered in divided doses of two, three orfour times daily. Furthermore, preferred NMT inhibitors of the presentinvention can be administered in intranasal form via topical use ofsuitable intranasal vehicles, or via transdermal routes, using thoseforms of transdermal skin patches well known to those of ordinary skillin the art. To be administered in the form of a transdermal deliverysystem, the dosage administration will, of course, be continuous ratherthan intermittent throughout the dosage regimen.

While it is possible for the active ingredient to be administered alone,it is preferable for it to be present in a pharmaceutical formulation orcomposition. Accordingly, the invention provides a pharmaceuticalformulation or composition comprising an NMT inhibitor according to theinvention, and a pharmaceutically acceptable diluent, excipient orcarrier (collectively referred to herein as “carrier” materials).Pharmaceutical compositions of the invention may take the form of apharmaceutical formulation as described below.

The pharmaceutical formulations according to the invention include thosesuitable for oral, parenteral (including subcutaneous, intradermal,intramuscular, intravenous [bolus or infusion], and intraarticular),intranasal (also known as nasal administration), inhalation (includingfine particle dusts or mists which may be generated by means of varioustypes of metered dose pressurized aerosols, nebulizers or insufflators)insufflation, rectal, intraperitoneal and topical (including dermal,buccal, sublingual, and intraocular) administration, although the mostsuitable route may depend upon, for example, the condition and disorderof the recipient.

In certain preferred embodiments the NMT inhibitor according to thepresent invention is administered by intranasal, inhalation (includingfine particle dusts or mists which may be generated by means of varioustypes of metered dose pressurized aerosols, nebulizers or insufflators)or insufflation administration. Such embodiments are especiallypreferred for, for example, the treatment of a picornaviarl infection,such as human rhinovirus infection. Such a method of administrationallows for low doses of NMT inhibitor to be administered, which can leadto a reduction in side-effects. For example, a daily dose of 10 to 0.01μg, preferably 1 to 0.01 μg, and more preferably in the region of as lowas 0.1 μg (100 ng) of NMT inhibitor may be used.

The formulations may conveniently be presented in unit dosage form andmay be prepared by any of the methods well known in the art of pharmacy.All methods include the step of bringing the active ingredient intoassociation with the carrier which constitutes one or more accessoryingredients. In general the formulations are prepared by uniformly andintimately bringing into association the active ingredient with liquidcarriers or finely divided solid carriers or both and then, ifnecessary, shaping the product into the desired formulation.

Formulations of the present invention suitable for oral administrationmay be presented as discrete units such as capsules, cachets, pills ortablets each containing a predetermined amount of the active ingredient;as a powder or granules; as a solution or a suspension in an aqueousliquid or a non-aqueous liquid, for example as elixirs, tinctures,suspensions or syrups; or as an oil-in-water liquid emulsion or awater-in-oil liquid emulsion. The active ingredient may also bepresented as a bolus, electuary or paste.

A tablet may be made by compression or moulding, optionally with one ormore accessory ingredients. Compressed tablets may be prepared bycompressing in a suitable machine the active ingredient in afree-flowing form such as a powder or granules, optionally mixed with abinder, lubricant, inert diluent, lubricating, surface active ordispersing agent. Moulded tablets may be made by moulding in a suitablemachine a mixture of the powdered compound moistened with an inertliquid diluent. The tablets may optionally be coated or scored and maybe formulated so as to provide slow or controlled release of the activeingredient therein. The present NMT inhibitors can, for example, beadministered in a form suitable for immediate release or extendedrelease. Immediate release or extended release can be achieved by theuse of suitable pharmaceutical compositions comprising the present NMTinhibitors, or, particularly in the case of extended release, by the useof devices such as subcutaneous implants or osmotic pumps. The presentNMT inhibitors may also be administered liposomally.

Exemplary compositions for oral administration include suspensions whichcan contain, for example, microcrystalline cellulose for imparting bulk,alginic acid or sodium alginate as a suspending agent, methylcelluloseas a viscosity enhancer, and sweeteners or flavoring agents such asthose known in the art; and immediate release tablets which can contain,for example, microcrystalline cellulose, dicalcium phosphate, starch,magnesium stearate, calcium sulfate, sorbitol, glucose and/or lactoseand/or other excipients, binders, extenders, disintegrants, diluents andlubricants such as those known in the art. Suitable binders includestarch, gelatin, natural sugars such as glucose or beta-lactose, cornsweeteners, natural and synthetic gums such as acacia, tragacanth orsodium alginate, carboxymethylcellulose, polyethylene glycol, waxes andthe like. Disintegrators include without limitation starch,methylcellulose, agar, bentonite, xanthan gum and the like. The NMTinhibitors according to the invention can also be delivered through theoral cavity by sublingual and/or buccal administration. Molded tablets,compressed tablets or freeze-dried tablets are exemplary forms which maybe used. Exemplary compositions include those formulating the presentNMT inhibitors with fast dissolving diluents such as mannitol, lactose,sucrose and/or cyclodextrins. Also included in such formulations may behigh molecular weight excipients such as celluloses (avicel) orpolyethylene glycols (PEG). Such formulations can also include anexcipient to aid mucosal adhesion such as hydroxy propyl cellulose(HPC), hydroxy propyl methyl cellulose (HPMC), sodium carboxy methylcellulose (SCMC), maleic anhydride copolymer (e.g., Gantrez), and agentsto control release such as polyacrylic copolymer (e.g. Carbopol 934).Lubricants, glidants, flavors, coloring agents and stabilizers may alsobe added for ease of fabrication and use. Lubricants used in thesedosage forms include sodium oleate, sodium stearate, magnesium stearate,sodium benzoate, sodium acetate, sodium chloride and the like. For oraladministration in liquid form, the oral drug components can be combinedwith any oral, non-toxic, pharmaceutically acceptable inert carrier suchas ethanol, glycerol, water, and the like.

The NMT inhibitors of the present invention can also be administered inthe form of liposome delivery systems, such as small unilamellarvesicles, large unilamellar vesicles and multilamellar vesicles.Liposomes can be formed from a variety of phospholipids,1,2-dipalmitoylphosphatidylcholine, phosphatidyl ethanolamine(cephaline), or phosphatidylcholine (lecithin).

Formulations for parenteral administration include aqueous andnon-aqueous sterile injection solutions which may contain anti-oxidants,buffers, bacteriostats and solutes which render the formulation isotonicwith the blood of the intended recipient; and aqueous and non-aqueoussterile suspensions which may include suspending agents and thickeningagents.

The formulations may be presented in unit-dose or multi-dose containers,for example sealed ampoules and vials, and may be stored in afreeze-dried (lyophilised) condition requiring only the addition of thesterile liquid carrier, for example saline or water-for-injection,immediately prior to use. Extemporaneous injection solutions andsuspensions may be prepared from sterile powders, granules and tabletsof the kind previously described. Exemplary compositions for parenteraladministration include injectable solutions or suspensions which cancontain, for example, suitable non-toxic, parenterally acceptablediluents or solvents, such as mannitol, 1,3-butanediol, water, Ringer'ssolution, an isotonic sodium chloride solution, or other suitabledispersing or wetting and suspending agents, including synthetic mono-or diglycerides, and fatty acids, including oleic acid, or Cremaphor.

Exemplary compositions for intranasal, aerosol or inhalationadministration include solutions in saline, which can contain, forexample, benzyl alcohol or other suitable preservatives, absorptionpromoters to enhance bioavailability, and/or other solubilizing ordispersing agents such as those known in the art.

Formulations for rectal administration may be presented as a suppositorywith the usual carriers such as cocoa butter, synthetic glyceride estersor polyethylene glycol. Such carriers are typically solid at ordinarytemperatures, but liquefy and/or dissolve in the rectal cavity torelease the drug.

Formulations for topical administration in the mouth, for examplebuccally or sublingually, include lozenges comprising the activeingredient in a flavoured basis such as sucrose and acacia ortragacanth, and pastilles comprising the active ingredient in a basissuch as gelatin and glycerine or sucrose and acacia. Exemplarycompositions for topical administration include a topical carrier suchas Plastibase (mineral oil gelled with polyethylene).

Preferred unit dosage formulations are those containing an effectivedose, as hereinbefore recited, or an appropriate fraction thereof, ofthe active ingredient.

It should be understood that in addition to the ingredients particularlymentioned above, the formulations of this invention may include otheragents conventional in the art having regard to the type of formulationin question, for example those suitable for oral administration mayinclude flavouring agents.

Whilst an NMT inhibitor of the invention may be used as the sole activeingredient in a medicament, it is also possible for the NMT inhibitor tobe used in combination with one or more further therapeutic agents.Accordingly there is provided an NMT inhibitor of the invention,together with a further therapeutic ingredient, for simultaneous,sequential or separate administration.

Such further therapeutic agents may be further NMT inhibitors, forexample a further NMT inhibitor according to the invention (i.e. afurther compound of formula (I) or salt thereof).

Further therapeutic agents may also be different therapeutic agents; forexample further therapeutic agents useful for treatment of malaria,leishmaniasis, human African trypanosomiasis (sleeping sickness) andAmerican trypanosomiasis (Chagas disease); anti-fungal agents;anti-viral agents (including anti-HIV agents); chemotherapeutic agents(e.g. anti-lymphoma agents); antidepressants; anxiolytic agents;anti-psychotic agents; anti-osteoporosis agents; anti-ischemia agentsand/or anti-diabetic agents.

In one preferred embodiment, the NMT inhibitor of the invention isadministered in combination with an effective amount of a furtheranti-protozoan agent, for example (i) an anti-malarial agent selectedfrom the group consisting of chloroquine, primaquine, amodiaquine.mefloquine, halofantrine, lumefantrine, pyrimethamine, sulfadoxine,artemesinin, dihydroartemesinin, artemether, artesunate, atovaquone, andproguanil; and/or (ii) an anti-leishmaniasis agent selected from thegroup consisting of amphotericin B, miltefosine, paromomycin,pentamidine, fexinidazole, and meglumine antimonate; and/or (iii) ananti-human African trypanosomiasis or anti-American trypanosomiasisagent selected from the group consisting of melarsoprol, suramin,pentamidine, eflornithine, nufurtimox, benznidazole, posaconazole andE1224. One or more of those further anti-protozoan agents may be used incombination with an NMT inhibitor of the invention.

In a further embodiment, the NMT inhibitor of the invention may beeffectively administered in combination with an effective amount of ananti-lymphoma agent selected from the group consisting of adriamycin,bleomycin, blenoxane, dacarbazine, deltasone, cyclophosphamide, Cytoxan,DTIC, doxorubicin, etoposide, matulane, mechlorethamine, Mustargen,Mustine, Natulan, VCR, Neosar, nitrogen mustard, Oncovin, Orasone,Prednisone, procarbazine, VP-16, Velban, Velbe, Velsar, VePesid,vinblastine and vincristine.

The NMT inhibitors of the invention can be used in combination withother agents useful for the treatment or prophylaxis of a disease ordisorder in which inhibition of N-myristoyl transferase provides atherapeutic or prophylactic effect. The individual components of suchcombinations can be administered separately at different times duringthe course of therapy or concurrently in divided or single combinationforms. The present invention is therefore to be understood as embracingall such regimes of simultaneous or alternating treatment and the term“administering” is to be interpreted accordingly. It will be understoodthat the scope of combinations of the NMT inhibitors of the inventionwith other agents useful for treating or prophylaxis of a disease ordisorder in which inhibition of N-myristoyl transferase provides atherapeutic or prophylactic effect includes in principle any combinationwith any pharmaceutical composition useful for treating or prophylaxisof a disease or disorder in which inhibition of N-myristoyl transferaseprovides a therapeutic or prophylactic effect.

The above further therapeutic agents, when employed in combination withthe compounds of the present invention, may be used, for example, inthose amounts indicated in the Physicians' Desk Reference (PDR) or asotherwise determined by one of ordinary skill in the art.

Where the NMT inhibitors of the invention are utilized in combinationwith one or more further therapeutic agent(s), either concurrently orsequentially, the following combination ratios and dosage ranges arepreferred: when combined with a further therapeutic agent, the NMTinhibitor of the invention may for example be employed in a weight ratioto the further therapeutic agent within the range from about 10:1 toabout 1:10.

The invention also provides a kit of parts comprising: (a) a firstpharmaceutical composition comprising an NMT inhibitor according to theinvention and a pharmaceutically acceptable carrier; and (b) a secondpharmaceutical composition comprising a further therapeutic agent,preferably a further N-myristoyl transferase inhibitor, and apharmaceutically acceptable carrier.

In one embodiment, where the NMT inhibitor of the invention is for thetreatment treatment or prevention of rhinovirus (HRV, also known as thecommon cold), the NMT inhibitors of the invention may be utilized incombination with one or more further therapeutic agent(s), eitherconcurrently or sequentially, for the treatment of HRV and/or for thetreatment of asthma and/or for the treatment of chronic obstructivepulmonary disease (COPD). For example, the further therapeutic agent(s)may be selected from the group consisting of: pleconaril, pirodavir,vapendavir BTA-798, V-073, rupintrivir, enviroxime, IFN-β (SNG001);corticosteroids (inhaled and oral, for example beclomethasone,fluticasone, budesonide, ciclesonide), beta agonists (for examplesalbutamol, levosalbutamol, terbutaline, pirbuterol, procaterol,clenbuterol, metaproterenol, fenoterol, bitolterol mesylate, ritodrine,isoprenaline, salmeterol,

formoterol, bambuterol, clenbuterol, olodaterol and indacaterol)muscarinic antagonists (for example ipratropium and diphenhydramine),leukotriene receptor antagonists (for example montelukast, zafirlukast,zileuton), cromylins, PDE4 inhibitors (for example ibudilast), andanti-cytokine antibodies, such as anti-IgE (for example omalizumab),anti-IL5 (for example mepolizumab, reslizumab and benralizumab) anti-IL4(for example dupilumab and pitrakinra).

In one embodiment, the NMT inhibitor of the invention comprises anisotope atom, preferably a radioactive isotope atom. As defined herein,an isotope atom is an atom of an element that is not the most commonnaturally occurring isotope. Such NMT inhibitors may find use asdiagnostic agents for the diagnosis of a disease or disorder in whichinhibition of NMT provides a therapeutic or prophylactic effect.Accordingly, the present invention also provides for use of an NMTinhibitor comprising an isotope atom, preferably a radioactive isotopeatom, as a diagnostic agent for the diagnosis of a disease or disorderin which inhibition of NMT provides a therapeutic or prophylacticeffect.

The present invention also provides an NMT inhibitor in which L is—(CHR¹²)_(m)— or —(CHR¹²)_(m)O—, and one R¹² is a terminal C₁₋₆alkynyloptionally substituted by up to 3 —F, —Cl, —Br, I, —OH, —OCH₃, —OCF₃ or—CN groups (and more preferably one R¹² is a terminal unsubstitutedC₁₋₆alkynyl and/or when present, all other R¹² groups are hydrogen), foruse as a diagnostic agent for the diagnosis of a disease or disorder inwhich inhibition of NMT provides a therapeutic or prophylactic effect.In such an embodiment ‘click chemistry’, for example using an azideanalogue, can be used detect the NMT inhibitor.

The NMT inhibitors of the invention also find use as reference compoundsin methods of discovering other inhibitors of NMT. Thus, the inventionalso provides use of an NMT inhibitor according to the invention (i.e. acompound of formula (I) or salt thereof), for example an NMT inhibitorcomprising an isotope atom (preferably a radioactive isotope atom) or anNMT inhibitor in which L is —(CHR¹²)_(m)— or —(CHR¹²)_(m)O—, and one R¹²is a terminal C₁₋₆alkynyl optionally substituted by up to 3 —F, —Cl,—Br, I, —OH, —OCH₃, —OCF₃ or —CN groups, as a reference compound in amethod of identifying a further inhibitor of N-myristoyl transferase.For example, such a method may involve a competitive binding experimentin which binding of an NMT inhibitor according to the invention to anNMT enzyme is reduced by the presence of a further compound which hasNMT-binding characteristics, for example stronger NMT-bindingcharacteristics than the NMT inhibitor of the invention in question (i.ethe compound of formula (I) or salt thereof). In embodiments which usean NMT inhibitor in which L is —(CHR¹²)_(m)— or —(CHR¹²)_(m)O—, and oneR¹² is a terminal C₁₋₆alkynyl optionally substituted by up to 3 —F, —Cl,—Br, I, —OH, —OCH₃, —OCF₃ or —CN groups, ‘click chemistry’, for exampleusing an azide analogue, can be used detect the NMT inhibitor. In suchan embodiment, preferably one R¹² is a terminal unsubstitutedC₁₋₆alkynyl and/or, when present, all other R¹² groups are hydrogen

Numerous synthetic routes to the compounds of the present invention canbe devised by any person skilled in the art and the exemplifiedsynthetic routes described below do not limit the invention. Manymethods exist in the literature for the synthesis of heterocycles, forexample: Joule, J. A.; Mills, K., Heterocyclic Chemistry, 2010, 5^(th)Edition, Pub. Wiley. A number of possible synthetic routes areexemplified below. Where appropriate, any initially produced compoundaccording to the invention can be converted into another compoundaccording to the invention by known methods.

General Method I

The invention also provides a process for the preparation of an NMTinhibitor according to the invention, in which X and L are present; R⁴is hydrogen; R⁵ and R⁶ are each C₁₋₆alkyl; K is carbon; Q is N(R⁸); M isnitrogen; and R⁸ is hydrogen; the process comprising: (i) reacting acompound of formula (X)

in which Ms represents —S(O)₂CH₃; Pg represents a protecting group,preferably a 2-tetrahydropyranyl group; K is carbon; M is nitrogen; andE, J, G, R², R³ and s are as defined in formula (I);

with a compound of formula (XI)

HNR⁵R⁶  (XI)

in which R⁵ and R⁶ are each C₁₋₆alkyl;

and a source of hydride to produce a compound of formula (XII)

(ii) reacting the compound of formula (XII) with a compound of formula(XIII)

A-L-XH  (XIII)

in which L and X are present, and in which A, L and X are as defined informula (I); to produce a compound of formula (XIV)

(iii) subjecting the compound of formula (XIV) to deprotectionconditions to produce a compound of formula (I); and

(iv) optionally converting the compound of formula (I) to apharmaceutically acceptable salt thereof.

The compound of formula (X) may for example be produced by reacting acompound of formula (XIX)

in which Pg represents a protecting group, preferably a2-tetrahydropyranyl group; K is carbon; M is nitrogen; and E, J, G, R²,R³ and s are as defined in formula (I); with methanesulfonyl chloride inthe presence of a base such as triethylamine.

The compound of formula (XIX) may for example be produced reacting acompound of formula (XX)

in which Pg represents a protecting group, preferably a2-tetrahydropyranyl group; K is carbon; M is nitrogen; and E, J, G, andR³ are as defined in formula (I);

with a compound of formula (XXI)

in which each R^(A) independently represents hydrogen, C₁₋₆ alkyl, orthe two OR^(A) groups together form a —O—C(CH₃)₂—C(CH₃)₂—O— group;

under Suzuki coupling conditions; e.g. in the presence of a palladiumcatalyst such as tetrakis (triphenylphosphine)palladium(0) and a basesuch as potassium phosphate.

Where Pg represents a 2-tetrahydropyranyl group, the step of subjectingthe compound of formula (XIV) to deprotection conditions to produce acompound of formula (I) may comprise contacting the compound of formula(XIV) with an acid (e.g. HCl).

General Method I as shown above was used for the synthesis of, forexample, Example compounds 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13,14, 15 and 16. Full experimental details of the individual steps of thegeneral method applicable for the synthesis of Example compounds 1, 2,3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 and 16 are described below.

General Method II

The invention also provides a process for the preparation of an NMTinhibitor according to the invention in which X and L are present; K iscarbon; Q is N(R⁸); M is nitrogen; R⁴ is hydrogen; R⁸ is methyl; and R⁵and R⁶ are each C₁₋₆alkyl; the process comprising:

(i) reacting a compound of formula (XV)

in which Ms represents —S(O)₂CH₃; K is carbon; Q is N(R⁸); M isnitrogen; R⁸ is methyl; R⁴ is hydrogen; R⁵ and R⁶ are each C₁₋₆alkyl;and E, J, G, R², R³, R⁵, R⁶ and s are as defined in formula (I);

with a compound of formula (XIII)

A-L-XH  (XIII);

in which L and X are present, and in which A, L and X are as defined informula (I); to produce a compound of formula (I); and

(ii) optionally converting the compound of formula (I) to apharmaceutically acceptable salt thereof.

The compound of formula (XV) may for example be produced by reacting acompound of formula (XXII)

in which Ms represents —S(O)₂CH₃; K is carbon; Q is N(R⁸); M isnitrogen; R⁸ is methyl; and E, J, G, R², R³ and s are as defined informula (I);

with a compound of formula (XI)

HNR⁵R⁶  (XI)

in which R⁵ and R⁶ are each C₁₋₆alkyl;

and a source of hydride.

The compound of formula (XXII) may for example be produced by reacting acompound of formula (XXIII)

in which K is carbon; Q is N(R⁸); M is nitrogen; R⁸ is methyl; and E, J,G, R², R³ and s are as defined in formula (I);

with methanesulfonyl chloride in the presence of a base such astriethylamine.

The compound of formula (XXIII) may for example be produced by reactinga compound of formula (XXIV)

in which K is carbon; Q is N(R⁸); M is nitrogen; R⁸ is methyl; and E, J,G and R³ are as defined in formula (I);

with a compound of formula (XXI) as defined above, under Suzuki couplingconditions, e.g. in the presence of a palladium catalyst such astetrakis (triphenylphosphine)palladium(0) and a base such as potassiumphosphate.

General Method II as shown above was used for the synthesis of, forexample, Example compound 20, 21, 22, 23 and 24. Full experimentaldetails of the individual steps of the general method applicable for thesynthesis of Example compound 20, 21 22, 23 and 24 are described below.

General Method III

The invention also provides a process for the preparation of an NMTinhibitor according to the invention in which X and L are present; K iscarbon; Q is N(R⁸); M is nitrogen; R⁸ is methyl; and R⁵ and R⁶ are eachhydrogen; the process comprising:

(i) reacting a compound of formula (XVI)

in which Ms represents —S(O)₂CH₃; K is carbon; Q is N(R⁸); M isnitrogen; R⁸ is methyl; Pg′ is a protecting group, preferably a benzoylgroup; and E, J, G, R², R³ R⁴ and s are as defined in formula (I);

with a compound of formula (XIII)

A-L-XH  (XIII);

In which L and X are present, and in which A, L and X are as defined informula (I); to produce a compound of formula (XVII)

(ii) subjecting the compound of formula (XVII) to deprotectionconditions to produce a compound of formula (I); and

(iii) optionally converting the compound of formula (I) to apharmaceutically acceptable salt thereof.

Where Pg′ represents a benzoyl group, the step of subjecting thecompound of formula (XVII) to deprotection conditions to produce acompound of formula (I) may comprise contacting the compound of formula(XVII) with an acid (e.g. HCl).

General Method IV

The invention also provides a process for the preparation of an NMTinhibitor according to the invention in which R⁴ is hydrogen; K iscarbon; Q is N(R⁸); M is nitrogen; and R⁸ is methyl; the processcomprising:

(i) reacting a compound of formula (XVIII)

in which K is carbon; Q is N(R⁸); M is nitrogen; R⁸ is methyl; and E, J,G, R¹, R², R³ and s are as defined in formula (I);

with a compound of formula (XI)

HNR⁵R⁸  (XI)

in which R⁵ and R⁸ are as defined as in formula (I);

and a source of hydride to produce a compound of formula (I);

(ii) optionally converting the compound of formula (I) into a furthercompound of formula (I); and

(iii) optionally converting the compound of formula (I) to apharmaceutically acceptable salt thereof.

Where L and X are present, the compound of formula (XVIII) may forexample be produced by reacting a compound of formula (XXV)

in which K is carbon; Q is N(R⁸); M is nitrogen; R⁸ is methyl; and E, J,G, R², R³ and s are as defined in formula (I);

with a compound of formula (XIII)

A-L-XH  (XIII);

in which L and X are present, and in which A, L and X are as defined informula (I); under Mitsunobu conditions, for example usingtriphenylphosphine and di-isopropyl azodicarboxylate.

Alternatively, where L and X are present, the compound of formula(XVIII) may for example be produced by reacting a compound of formula(XXII)

in which Ms represents S(O)₂CH₃; K is carbon; Q is N(R⁸); M is nitrogen;R^(a) is methyl; and E, J, G, R², R³ and s are as defined in formula(I);

with a compound of formula (XIII)

A-L-XH  (XIII);

in which L and X are present, and in which A, L and X are as defined informula (I).

The compound of formula (I) where R⁵ and R⁶ are each hydrogen may beconverted into a further compound of formula (I) where R⁵ and R⁶ areeach methyl, for example by reacting with paraformaldehyde and aceticacid, followed by sodium acetoxyborohydride.

The compound of formula (I) where R⁵ and R⁶ are each hydrogen may beconverted into a further compound of formula (I) where R⁵ is methyl andR⁶ is hydrogen, for example by i) conversion of the primary amine group(i.e. —NR⁵R⁶, wherein both R⁵ and R⁶ are hydrogen) into thecorresponding formyl amide (i.e. —NH—CH(O)) or into a carbamate,followed by ii) reduction (e.g. with lithium aluminium hydride) toproduce the further compound of formula (I) where R⁵ is methyl and R⁶ ishydrogen.

General Method IV as-shown above was used for the synthesis of, forexample, Example compounds 17, 18, 25, 26, 29, 30. Full experimentaldetails of the individual steps of the general method applicable for thesynthesis of Example compounds 17, 18, 25, 26, 29, 30 are describedbelow.

General Method V

The invention also provides a process for the preparation of an NMTinhibitor according to the invention in which R³, R⁴, R⁵ and R⁶ are eachhydrogen; K is carbon; Q is N(R⁸); M is nitrogen; and R^(a) is methyl;the process comprising:

(i) reacting a compound of formula (XIX)

in which K is carbon; Q is N(R⁸); M is nitrogen; R⁸ is methyl; and E, J,G, R¹, R² and s are as defined in formula (I);

with a reducing agent to produce a compound of formula (I); and

(ii) optionally converting the compound of formula (I) to apharmaceutically acceptable salt thereof.

The compound of formula (XIX) may for example be produced by reacting acompound of formula (XXVI)

in which K is carbon; Q is N(R⁸); M is nitrogen; R⁸ is methyl; and E, J,G, R¹, R² and s are as defined in formula (I);

with hydroxylamine hydrochloride and sodium acetate.

General Method V as shown above was used for the synthesis of, forexample, Example compounds 31, 32 and 33. Full experimental details ofthe individual steps of the general method applicable for the synthesisof Example compounds 31, 32 and 33 are described below.

General Method VI

The invention also provides a process for the preparation of an NMTinhibitor according to the invention in which X and L are present; R⁵and R⁶ are each C₁₋₆alkyl; K, Q and M are each nitrogen; the processcomprising:

(i) reacting a compound of formula (XV)

in which Ms represents —S(O)₂CH₃; K, Q and M are each nitrogen; R⁵ andR⁶ are each C₁₋₆alkyl; and E, J, G, R², R³ R⁴ and s are as defined informula (I);

with a compound of formula (XIII)

A-L-XH  (XIII);

in which L and X are present, and in which A, L and X are as defined informula (I); to produce a compound of formula (I); and

(ii) optionally converting the compound of formula (I) to apharmaceutically acceptable salt thereof.

General Method VII

The invention also provides a process for the preparation of an NMTinhibitor according to the invention in which X and L are present; R⁵and R⁶ are each hydrogen; and K, Q and M are each nitrogen; the processcomprising:

(i) reacting a compound of formula (XVI)

in which Ms represents —S(O)₂CH₃; K, Q and M are each nitrogen; Pg′ is aprotecting group, preferably a benzoyl group; and E, J, G, R², R³, R⁴and s are as defined in formula (I); with a compound of formula (XIII)

A-L-XH  (XIII);

in which L and X are present, and A, L and X are as defined in formula(I);

to produce a compound of formula (XVII)

(ii) subjecting the compound of formula (XVII) to deprotectionconditions to produce a compound of formula (I);

(iii) optionally concerting the compound of formula (I) into a furthercompound of formula (I); and

(iv) optionally converting the compound of formula (I) to apharmaceutically acceptable salt thereof.

Where Pg′ represents a benzoyl group, the step of subjecting thecompound of formula (XVII) to deprotection conditions to produce acompound of formula (I) may comprise contacting the compound of formula(XVII) with an acid (e.g. HCl).

The compound of formula (I) where R⁵ and R⁶ are each hydrogen may beconverted into a further compound of formula (I) where R⁵ and R⁶ areeach methyl, for example by reacting with paraformaldehyde and aceticacid, followed by sodium acetoxyborohydride.

Where Pg′ is a benzoyl group, the compound of formula (XVI) may forexample be produced by reaction of a compound of formula (XXVII)

in which K, Q and M are each nitrogen; and E, J, G, R², R³, R⁴ and s areas defined in formula (I);

with methanesulfonyl chloride in the presence of a base such astriethylamine.

The compound of formula (XXVII) may for example be produced by reactionof a compound of formula (XXVIII)

in which K, Q and M are each nitrogen; and E, J, G, R³ and R⁴ are asdefined in formula (I); with a compound of formula (XXI) as definedabove, under Suzuki coupling conditions, e.g. in the presence of apalladium catalyst such as tetrakis (triphenylphosphine)palladium(0) anda base such as potassium phosphate.

Where Pg′ is benzoyl, where E, J, and G are each CH, and where K, Q andM are each nitrogen, the compound of formula (XXVIII) may for example beproduced by reacting a compound of formula (XXIX)

with a compound of formula (XXX)

in which R³ and R⁴ are as defined in formula (I).

General Method VII as shown above was used for the synthesis of, forexample, Example compounds 27 and 28. Full experimental details of theindividual steps of the general method applicable for the synthesis ofExample compounds 27 and 28 are described below.

General Method VIII

The invention also provides a process for the preparation of an NMTinhibitor according to the invention in which X is O, L is present; K iscarbon; Q is N(R⁸); M is nitrogen; R⁴ is hydrogen; R⁸ is methyl; and R⁵and R⁶ are each C₁₋₆alkyl; the process comprising:

(i) reacting a compound of formula (XL)

in which; K is carbon; Q is N(R⁸); M is nitrogen; R⁸ is methyl; R⁴ ishydrogen; R⁵ and R⁶ are each C₁₋₆alkyl; and E, J, G, R², R³, R⁵, R⁶ ands are as defined in formula (I); with a compound of formula (XLI)

A-L-O-Ts  (XLI);

in which Ts represents a para-toluene-sulfonyl group; L is present; andA and L are as defined in formula (I);

to produce a compound of formula (I); and

(ii) optionally converting the compound of formula (I) to apharmaceutically acceptable salt thereof.

The compound of formula (XL) may for example be produced by reacting acompound of formula (XLII)

in which; K is carbon; Q is N(R⁸); M is nitrogen; R⁶ is methyl; and E,J, G, R², R³ and s are as defined in formula (I);

with a compound of formula (XI)

HNR⁵R⁶  (XI)

in which R⁵ and R⁶ are each C₁₋₆alkyl;

and a source of hydride.

General Method VIII as shown above was used for the synthesis of, forexample, Example compound 19. Full experimental details of theindividual steps of the general method applicable for the synthesis ofExample compound 19 are described below.

Synthesis of Example Compounds General Experimental Details

LC-MS

Compounds were purified and analysed on an LC-MS system equipped withboth an XBridge prep C18 5 μm, 19×100 mm OBD column and an XBridge C18 5μm, 4.6×100 mm column. Unless specified otherwise, all compounds wereseparated over a gradient of methanol in water (5-98% over 12 minutesthen 98% methanol for 3 minutes), both containing 0.1% formic acid.Alternative gradient elutions started from 20 or 50% methanol for thesame time periods.

Compounds requiring purification under basic conditions were purified onan LC-MS system equipped with a YMC Actus Triart C18 5 μm (20×250 mm)column or Gemini NX 5 μm C18 (100×30 mm) columns, using a gradientelution of acetonitrile in water containing 20 mM Ammonium bicarbonate(10-45% over 30 min then 95% acetonitrile for 2 minutes).

Hplc

The purity of examples 53-108 (with the exception of examples 74, 75,79-82, 87-89 and 96) was determined by analytical hplc using an EclipseExtend 5 μm C18 (150×4.6 mm) or Shimadzu L Column 2 ODS 5 μm C18(150×4.6 mm) column using gradient elution of acetonitrile in watercontaining 10 mM ammonium acetate over 12 mins. The purity of examples87-89 and 96 were determined by analytical hplc using a Gemini NX 3 μmC18 (50×4.6 mm) column using gradient elution of acetonitrile in watercontaining 0.05% formic acid over 12 mins.

Flash Column Chromatography

Compounds were purified using either an automated system usingpre-packed silica cartridges and a gradient of ethyl acetate in n-hexane(typically 5-30% over 20 minutes) with UV detection or by manual columnsusing an appropriate solvent mixture as detailed.

NMR

¹H NMR and ¹³C spectra were recorded on 400 MHz and 101 MHz respectivelyinstruments at room temperature unless specified otherwise werereferenced to residual solvent signals. Data are presented as follows:chemical shift in ppm, integration, multiplicity (br=broad,app=apparent, s=singlet, d=doublet, t=triplet, q=quartet, p=pentet,m=multiplet) and coupling constants in Hz.

General Procedures THP Deprotection (Method A)

The THP (tetrahydropyranyl) protected indazole was dissolved in a 1:1mixture of THF and methanol (2 ml), then treated with a solution of HClin isopropanol (6M, 1 ml). The reaction mixture was left at roomtemperature for 2 days. All volatiles were removed under reducedpressure and the residue was partitioned between ethyl acetate (20 ml)and saturated sodium carbonate solution (10 ml). The organic phase wasdried over Na₂SO₄, concentrated under reduced pressure and the crudeproduct purified by flash column chromatography.

THP Deprotection (Method B)

The THP protected indazole was dissolved in a 1:1 mixture of THF andmethanol (2 ml), then treated with a solution of HCl in isopropanol (6M,1 ml). The reaction mixture was heated to 40° C. at room temperature for6 h-2 days. All volatiles were removed under reduced pressure and theresidue was partitioned between ethyl acetate (20 ml) and saturatedsodium carbonate solution (10 ml). The organic phase was dried overNa₂SO₄, concentrated under reduced pressure and the product purified byLC-MS.

Reductive Amination (Method A)

A solution of the heterocyclic carboxaldehydes (e.g. theindazolecarboxaldehyde) in DCE (dichloroethane) (5 ml) was treated witha solution of the appropriate amine in THF (3 mol equiv) followed byacetic acid (6 mol equiv). The solution was stirred at room temperaturefor 15 mins before being treated with solid sodium triacetoxyborohydride(3 mol equiv). The mixture was stirred overnight at room temperaturethen partitioned between DCM (dichloromethane) (20 ml) and saturatedsodium carbonate solution (10 ml). The organic phase was dried overNa₂SO₄, concentrated under reduced pressure and the crude productpurified by flash column chromatography by elution with ethylacetate/methanol/diethylamine (95:0:5, then 92:3:5).

Reductive Amination (Method B)

The heterocyclic carboxaldehydes (e.g. the indazolecarboxaldehyde) wasdissolved in a solution of the appropriate amine in ethanol (2 ml) andthe solution stirred at room temperature overnight. Volatile materialwas removed under reduced pressure and residue dissolved in ethanol (5ml), then treated with solid sodium borohydride (5 mol equiv). Afterstirring for 3 hours at room temperature, excess regent was destroyed byaddition of 1N HCl and the mixture concentrated in vacuo. The residuewas partitioned between ethyl acetate (20 ml) and saturated sodiumcarbonate solution (10 ml). The organic phase was dried over Na₂SO₄,concentrated under reduced pressure and the crude product purified byflash column chromatography by elution with ethylacetate/methanol/diethylamine (95:0:5, then 90:5:5).

Reductive Amination (Method C).

The 3-acetylindazole was dissolved in methanol (2 ml) and treated withammonium acetate (10 mol equiv) followed by sodium cyanoborohydride (5mol equiv). The solution stirred and heated under reflux overnight.Volatile material was removed under reduced residue was partitionedbetween dichloromethane (20 ml) and saturated sodium carbonate solution(10 ml). The organic phase was dried over Na₂SO₄, concentrated underreduced pressure and the crude product purified by flash columnchromatography by elution dichloromethane/methanol/conc.aqueous ammoniasolution (97:3:0.5, then 95:5:0.5).

Reductive Amination (Method D)

A solution of the aminoalkyl heterocycles (e.g. the aminoalkylindazole)in DCE (5 ml) was treated with solid paraformaldehyde (10 mol equiv) andacetic acid (8 mol equiv). The suspension was stirred at roomtemperature for 15 mins before being treated with solid sodiumtriacetoxyborohydride (8 mol equiv). The mixture was stirred overnightat room temperature then partitioned between DCM (20 ml) and saturatedsodium carbonate solution (10 ml). The organic phase was dried overNa₂SO₄, concentrated under reduced pressure and the crude productpurified LC-MS.

Reductive Amination (Method E)

A solution of the heterocyclic carboxaldehydes (e.g. theindazolecarboxaldehyde) in THF (2 mL) was treated with a solution of theappropriate amine in THF (tetrahydrofuran) (3 mol equiv) followed byacetic acid (6 mol equiv). The solution was stirred at room temperaturefor 15 mins before being treated with solid sodium triacetoxyborohydride(3 mol equiv) and DCE (2 mL). The mixture was stirred overnight at roomtemperature then partitioned between DCM (20 mL) and saturated sodiumcarbonate solution (10 mL). The organic phase was dried over Na₂SO₄,concentrated under reduced pressure and the crude product purified byLCMS.

Mesyl Transfer (Method A)

A solution of the appropriate phenylmethane sulphonate in dryacetonitrile in a microwave vial was treated with a solution of theappropriate alcohol (1 mol equiv), followed by solid sodium t-butoxide(1 mol equiv). The vial was sealed then heated under microwaveirradiation to 140° C. for 10 mins. The reaction mixture was partitionedbetween ethyl acetate (20 ml) and saturated sodium carbonate solution(10 ml). The organic phase was dried over Na₂SO₄, concentrated underreduced pressure and the crude product purified by flash columnchromatography by elution with ethyl acetate/methanol/diethylamine(95:0:5, optionally by further elution with a 90:5:5 mixture).

Mesyl Transfer (Method B)

A solution of the appropriate phenylmethane sulphonate in dry DMF(N,N-dimethylformamide) (5 ml) was treated with a solution of theappropriate alcohol (1.5 mol equiv), followed by solid cesium carbonate(1.1 mol equiv). The reaction mixture was heated to 100° C. for 18 hrs,cooled to room temperature then partitioned between ethyl acetate (20ml) and saturated sodium carbonate solution (10 ml). The organic phasewas dried over Na₂SO₄, concentrated under reduced pressure and the crudeproduct purified by flash column chromatography by elution with ethylacetate/methanol/diethylamine (95:0:5, then 90:5:5) ordichloromethane/methanol/aqueous ammonia solution (95:5:0.5).

Mesyl Transfer (Method C)

A solution of the appropriate alcohol (1.0 mol equiv) was added to asuspension of sodium hydride (50% dispersion in oil, 1.9 mol equiv) indry DMF followed by a solution of the appropriate phenylmethanesulphonate (1.0 mol equiv) in dry DMF. The reaction mixture was heatedto 70° C. for 18 hrs, cooled to room temperature then partitionedbetween ethyl acetate (20 ml) and saturated sodium carbonate solution(10 ml). The organic phase was dried over Na₂SO₄, concentrated underreduced pressure and the crude product purified by flash columnchromatography by elution with ethyl acetate/methanol/diethylamine(95:0:5, then 90:5:5) or dichloromethane/methanol/aqueous ammoniasolution (95:5:0.5).

Mesyl Transfer (Method D)

A solution of the appropriate phenylmethane sulphonate in dry DMF in amicrowave vial was treated with a solution of the appropriate alcohol (2mol equiv), followed by solid cesium carbonate (2 mol equiv). The vialwas sealed then heated under microwave irradiation to 140° C. for 10mins. The reaction mixture was partitioned between ethyl acetate (20 ml)and saturated sodium carbonate solution (10 ml). The organic phase wasdried over Na₂SO₄, concentrated under reduced pressure and the crudeproduct purified by flash column chromatography by elution with ethylacetate/methanol/diethylamine (95:0:5, optionally by further elutionwith a 90:5:5 mixture).

Mesyl Transfer (Method E)

A solution of the appropriate phenylmethane sulphonate in dryacetonitrile in a microwave vial was treated with a solution of theappropriate alcohol (5 mol equiv), followed by solid cesium carbonate (2mol equiv). The vial was sealed then heated under microwave irradiationto 140° C. for 20 mins. The reaction mixture was partitioned betweenethyl acetate (20 ml) and saturated sodium carbonate solution (10 ml).The organic phase was dried over Na₂SO₄, concentrated under reducedpressure and the crude product purified by flash column chromatographyby elution with ethyl acetate/methanol/diethylamine (95:0:5, optionallyby further elution with a 90:5:5 mixture).

Alkylation Using Alkyltosylate

A solution of the appropriate phenol in dry acetonitrile (0.5 ml) in amicrowave vial was treated with a solution of the appropriatealcoholtosylate (1.1 mol equiv), followed by solid sodium t-butoxide (1mol equiv). The vial was sealed then heated under microwave irradiationto 140° C. for 10 mins. The reaction mixture was partitioned betweenethyl acetate (20 ml) and saturated sodium carbonate solution (10 ml).The organic phase was dried over Na₂SO₄, concentrated under reducedpressure and the crude product purified by flash column chromatographyby elution with ethyl acetate/methanol/diethylamine (95:0:5, then90:5:5) or dichloromethane/methanol/aqueous ammonia solution (95:5:0.5).

Benzamide Deprotection

The appropriate benzamide was dissolved in concentrated hydrochloricacid and heated under reflux overnight. The mixture was evaporated todryness under reduced pressure, redissolved in methanol and basifiedwith a solution of ammonia in methanol (7M, 5 ml), then re-evaporated.The crude product was purified by column chromatography on silica byelution with dichloromethane/methanol/ammonium hydroxide (90:10:1).

Boc Deprotection (Method A)

The Boc protected amine was dissolved in a 1:1 mixture of THF andmethanol (2 ml), then treated with a solution of HCl in isopropanol (6M,1 ml). The reaction mixture was stirred at room temperature overnight.All volatiles were removed under reduced pressure and the productpurified by LC-MS using a gradient elution from methanol/water/formicacid (5:95:0.1 to 98:2:0.1).

Boc Deprotection (Method B)

The Boc protected amine was dissolved in dioxane and treated with asolution of HCl in dioxane (6M, 2 ml). The reaction mixture was stirredat room temperature overnight. All volatiles were removed under reducedpressure and the product triturated with ether redissolved in water andfreeze dried.

Boc Deprotection (Method C)

The Boc protected amine was dissolved in dichloromethane then treatedwith trifluoroacetic acid at 0° C. The solution was stirred at roomtemperature for 3 hr. The solvent was removed under reduced pressure andthe residue triturated with diethyl ether. The product was dissolved inwater and freeze-dried.

Preparation of Starting Materials

All of the starting materials for making the intermediate and examplecompound were obtained from commercial sources or using literaturemethods with the exception of the following compounds.

2-(3-isobutyl-1,5-dimethyl-1H-pyrazol-4-yl)ethanol and2-(5-isobutyl-1,3-dimethyl-1H-pyrazol-4-yl)ethanol

Step 1

A solution of 6-methylheptane-2,4-dione (5.0 g, 35 mmol) in DMF (20 ml)was added dropwise to a suspension of sodium hydride (50% dispersion inoil; 1.69 g, 42 mmol) in DMF(30 ml) at 0° C. The mixture was stirred for30 mins then treated with a solution of ethyl bromoacetate (4.3 ml, 39mmol) in DMF (20 ml). The reaction mixture was allowed to warm to roomtemperature, stirred overnight then quenched by addition of water (20ml). The solvents were removed under reduced pressure and the residuepartitioned between ethyl acetate (150 ml) and water (100 ml). Theorganic phase was dried (Na₂SO₄) and concentrated under reducedpressure. The crude product was purified by column chromatography byelution with ethyl acetate/hexane (5:95). Fractions containing theproduct were combined and evaporated to give a colourless oil (5.2 g),which was found to be an inseparable mixture of mono- and di-alkylatedproducts.

Step 2

The mixture of ethyl 3-acetyl-6-methyl-4-oxoheptanoate and diethyl3-acetyl-3-(3-methylbutanoyl)pentanedioate from Step 1 (5.2 g, −2.4mmol) was dissolved in acetic acid (50 ml) and treated withmethylhydrazine (1.4 m, 2.6 mmol) dropwise over 5 min. The solution wasstirred overnight at room temperature, then evaporated under reducedpressure. The residue was partitioned between ethyl acetate (100 ml) andsodium carbonate solution (2M, 100 ml). The organic phase was dried(Na₂SO₄) and concentrated under reduced pressure. The crude product waspurified by column chromatography by elution with ethyl acetate/hexane(50:50, then 75:25 and 100:0). Fractions containing unreacted diethyl3-acetyl-3-(3-methylbutanoyl)pentanedioate eluted first followed byfractions containing a mixture of both desired products, which werecombined and evaporated. Partial separation of the regiosomeric productswas achieved using column chromatography by elution with DCM/ethylacetate (70:30, then 50:50). Fractions containing the higher and lowerRf product spots were combined separately, then analysed by NMR and werefound to be 6:1 mixtures of the desired regioisomeric products. Thestructure of each compound was assigned by the nOe peaks between theN-methyl and the adjacent C—H groups.

The higher running spot (470 mg) was assigned as ethyl2-(3-isobutyl-1,5-dimethyl-1H-pyrazol-4-yl)acetate ¹H NMR (400 MHz,Chloroform-d) δ 4.11 (q, J=7.2 Hz, 2H), 3.72 (s, 3H), 3.33 (s, 2H), 2.41(d, J=7.3 Hz, 2H), 2.19 (s, 3H), 1.98-1.84 (m, 1H), 1.24 (td, J=7.2, 1.6Hz, 3H), 0.91 (d, J=6.8 Hz, 6H).

The lower running spot (860 mg) was assigned as ethyl2-(5-isobutyl-1,3-dimethyl-1H-pyrazol-4-yl)acetate ¹H NMR (400 MHz,Chloroform-d) δ 4.11 (q, J=7.1 Hz, 2H), 3.71 (s, 3H), 3.32 (s, 2H), 2.44(d, J=7.6 Hz, 2H), 2.19 (s, 3H), 1.90-1.79 (m, 1H), 1.23 (t, J=7.1 Hz,3H), 0.91 (d, J=6.8 Hz, 6H).

Step 3

The appropriate ethyl pyrazole acetate was dissolved in dry THF (10 ml)and was treated with a solution of lithium aluminium hydride in toluene(1M, 1 equivalent). After 3 hr at room temperature, the reaction wasworked up using standard Fieser conditions (water; 15% sodium hydroxidesolution; water @ x; x; 3x ml/g LAH). Solid Na₂SO₄ was added to ensurecomplete dryness and the mixture was filtered and concentrated underreduced pressure to give the title compounds as 6:1 mixtures ofregioisomers. 2-(3-isobutyl-1,5-dimethyl-1H-pyrazol-4-yl)ethanolcolourless oil (440 mg) ¹H NMR (400 MHz, Chloroform-d) δ 3.61 (s, 3H),3.53 (t, J=7.4 Hz, 2H), 2.54 (t, J=7.3 Hz, 2H), 2.31 (d, J=7.3 Hz, 2H),2.10 (s, 3H), 1.90-1.79 (m, 1H), 0.84 (d, J=6.7, 3.4 Hz, 6H).2-(5-isobutyl-1,3-dimethyl-1H-pyrazol-4-yl)ethanol colourless oil (751mg) ¹H NMR (400 MHz, Chloroform-d) δ 3.51 (s, 3H), 3.45 (t, J=7.7 Hz,2H), 2.45 (t, J=7.6 Hz, 2H), 2.27 (d, J=7.4 Hz, 2H), 2.00 (s, 3H),1.73-1.63 (m, 1H), 0.75 (d, J=6.8 Hz, 6H).

2-bromo-3-[2-(1,3,5-trimethyl-1H-pyrazol-4-yl)ethoxy]pyridine

Step 1

A solution of 2-bromo-3-hydroxypyridine (250 mg, 0.65 mmol) indichloromethane (10 ml) was cooled to 0° C. then treated withtriethylamine (842 μl, 6.0 mmol) followed by methanesulfonyl chloride(467 μl, 6.0 mmol). The reaction mixture was allowed to warm to roomtemperature and was stirred for 18 hours before being quenched withsodium bicarbonate solution (2M, 20 ml). Dichloromethane (20 ml) wasadded and the layers were separated. The organic phase was washed withwater and brine then dried (Na₂SO₄) and concentrated under reducedpressure to give the product, 2-bromopyridin-3-yl methanesulfonate as aviscous liquid (700 mg, 97%). ¹H NMR (400 MHz, DMSO-d6) δ 8.40 (dd, 1H),7.99 (dd, 1H), 7.59 (dd, 1H), 3.60 (s, 3H),

Step 2

According to the general method for mesyl transfer (method B), asolution of 2-bromopyridin-3-yl methanesulfonate (350 mg, 1.39 mmol) indry DMF (5 ml) was treated with a solution of the2-(1,3,5-trimethyl-1H-pyrazol-4-yl)ethanol (388 mg, 2.5 mmol) in dry DMF(2.0 ml), followed by solid cesium carbonate (615 mg, 1.89 mmol). Thereaction mixture was heated to 100° C. overnight. The reaction mixturewas partitioned between ethyl acetate (50 ml) and saturated sodiumbicarbonate solution (10 ml). The organic phase was washed with waterand brine, dried over Na₂SO₄, concentrated under reduced pressure andthe crude product purified by flash column chromatography by elutionwith dichloromethane/methanol (97:3) to provide the title compound as acolourless oil (100 mg; 23%) ¹H NMR (400 MHz, DMSO-d6) 7.94 (dd, 1H),7.47 (dd, 1H), 7.36 (dd, 1H), 4.06 (t, 2H), 3.60 (s, 3H), 2.77 (t, 2H),2.18 (s, 3H), 2.11 (s, 3H).

4-(2-hydroxyethyl)-N,N,1,5-tetramethyl-1H-pyrazole-3-carboxamide

Step I

A solution of 4-bromo-1,5-dimethyl-1H-pyrazole-3-carboxylic acid (500mg, 2.3 mmol) in dry THF (10 ml) was treated with HATU (1.04 g, 2.7mmol) and triethylamine (640 μl, 4.6 mmol) followed by a solution ofdimethylamine in THF (2M, 113 μl, 2.5 mmol). The reaction mixture wasstirred at room temperature overnight, diluted with ethyl acetate andwashed with saturated sodium bicarbonate, water and brine, dried overNa₂SO₄, concentrated under reduced pressure and the crude productpurified by flash column chromatography by elution withdichloromethane/methanol (98:2) to provide4-bromo-N,N,1,5-tetramethyl-1H-pyrazole-3-carboxamide as a brown solid(500 mg, 89%). ¹H NMR (400 MHz, DMSO-d6) 3.79 (s, 3H), 2.96 (s, 3H),2.86 (s, 3H), 2.25 (s, 3H).

Step 2

A solution of 4-bromo-N,N,1,5-tetramethyl-1H-pyrazole-3-carboxamide (320mg, 1.3 mmol) in dry DMF (10 ml) was treated with tributylvinylstannane(0.76 ml, 2.6 mmol). The mixture was purged with argon for 15 min beforeaddition of tetrakis(triphenylphosphine) palladium(0) (75 mg, 0.065mmol). The reaction was heated to 110° C. overnight, diluted with ethylacetate and washed with water and brine, dried over Na₂SO₄, concentratedunder reduced pressure and the crude product purified by flash columnchromatography by gradient elution with dichloromethane/methanol(96:4-95:5) to provide4-ethenyl-N,N,1,5-tetramethyl-1H-pyrazole-3-carboxamide as a solid (125mg). ¹H NMR (400 MHz, DMSO-d6) 6.54 (dd, 1H), 5.20 (d, 1H), 5.06 (d,1H), 3.73 (s, 3H), 2.95 (s, 3H), 2.90 (s, 3H), 2.29 (s, 3H).

Step 3

A solution of 4-ethenyl-N,N,1,5-tetramethyl-1H-pyrazole-3-carboxamide(175 mg, 0.90 mmol) in dioxane (10 ml) was cooled to 0° C. and treatedwith a solution of 9-BBN (0.5M in THF, 4.5 ml). The reaction was heatedto 100° C. overnight. The mixture was re-cooled to 0° C., and wastreated with ethanol (0.7 ml), 6N NaOH solution (0.35 ml), 50% H₂O₂ (0.6ml). The reaction mixture was heated at 50° C. for 2 hr diluted withethyl acetate and washed with water and brine, dried over Na₂SO₄,concentrated under reduced pressure and the crude product purified byflash column chromatography by elution with dichloromethane/methanol(97:3) to provide the title compound as a colourless oil (150 mg; 78%).¹H NMR (400 MHz, DMSO-d6) 4.64 (t, 1H) 4.25 (q, 2H), 3.71 (s, 3H), 3.06(s, 3H), 2.94 (s, 3H), 2.54 (t, 2H), 2.17 (s, 3H).

3,4-difluoro-2-hydroxybenzene boronic acid

A solution of 3,4-difluoro-2-methoxybenzene boronic acid (4.12 g, 22mmol) im dry DCM (100 ml) was treated with a solution of borontribromide in DCM (1M, 33 ml, 33 mmol). After stirring for 1 hr at roomtemperature, the reaction mixture was poured onto ice and extracted withDCM/methanol (3×100 ml). The combined organic layers were dried(Na₂SO₄), and evaporated under reduced pressure to give a purple solid.Trituration of the solid residue with DCM gave an analytical sample ofthe title compound as an off-white solid (400 mg) mp 130-135° C.

2,3-difluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol

To a stirred solution of 6-bromo-2,3-difluorophenol (2.0 g, 9.60 mmol)in dioxane (20 mL), bis pinacolato diboron (2.68 g, 10.5 mmol)) and KOAc(1.69 g, 17.3 mmol) was added and degassed with argon for 15 min.PdCl₂(dppf).DCM (0.628 g, 0.7 mmol) was added and the reaction mixturewas stirred at 90° C. for 16 h. The progress of the reaction wasmonitored by TLC. After completion of the reaction, the reaction mixturewas filtered through Celite and washed with 10% MeOH in DCM. Thereaction mixture was concentrated under reduced pressure. The residuewas dissolved in EtOAc and organic layer was washed with brine, driedover anhydrous Na₂SO₄ and concentrated under reduced pressure. Theresidue was purified by column chromatography to afford2,3-difluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (340mg, 14%). H NMR (400 MHz, CDCl₃) δ 6.94 (m, 1H), 6.70 (m, 1H), 1.42 &1.17 (2s, 12H).

2-{1,5-dimethyl-3-[(pyrrolidin-1-yl)carbonyl]-1H-pyrazol-4-yl}ethan-1-ol

Step 1

A solution of 4-bromo-1,5-dimethyl-1H-pyrazole-3-carboxylic acid (1.0 g,4.6 mmol) in dry THF (25 ml) was treated with triethylamine (1.9 mL,13.7 mmol) and HATU (2.60 g, 6.8 mmol), followed by pyrrolidine (450 μL,5.5 mmol). The reaction mixture was stirred at room temperatureovernight, diluted with ethyl acetate and washed with saturated sodiumbicarbonate, water and brine, dried over Na₂SO₄, concentrated underreduced pressure and the crude product purified by flash columnchromatography by elution with dichloromethane/methanol (97:3) toprovide 4-bromo-1,5-dimethyl-3-[(pyrrolidin-1-yl)carbonyl]-1H-pyrazole(1.0 g, 81%). ¹H NMR (400 MHz, DMSO-d₆) 3.80 (s, 3H), 3.51 (t, 2H), 3.41(t, 2H), 2.25 (s, 3H), 1.83 (m, 4H).

Step 2

A solution of4-bromo-1,5-dimethyl-3-[(pyrrolidin-1-yl)carbonyl]-1H-pyrazole (1.0 g,3.5 mmol) in dry DMF (20 ml) was treated with tributylvinylstannane (2.0mL, 9.0 mmol). The mixture was purged with argon for 15 min beforeaddition of tetrakis(triphenylphosphine) palladium(0) (201 mg, 0.174mmol). The reaction was heated to 110° C. overnight, diluted with ethylacetate and washed with water and brine, dried over Na₂SO₄, concentratedunder reduced pressure and the crude product purified by flash columnchromatography by gradient elution with dichloromethane/methanol (97:3)to provide4-ethenyl-1,5-dimethyl-3-[(pyrrolidin-1-yl)carbonyl]-1H-pyrazole as agum (400 mg, 52%). ¹H NMR (400 MHz, DMSO-d₆) 6.73 (dd, 1H), 5.27 (dd,1H), 5.08 (dd, 1H), 3.75 (s, 3H), 3.45 (dt, 4H), 2.30 (s, 3H), 1.81 (m,4H).

Step 3

A solution of4-ethenyl-1,5-dimethyl-3-[(pyrrolidin-1-yl)carbonyl]-1H-pyrazole (400mg, 1.8 mmol) in dioxane (20 ml) was treated with a solution of 9-BBN(0.5M in THF, 9 ml, 4.5 mmol). The reaction was heated to 100° C.overnight. The mixture was re-cooled to 0° C., and was treated withethanol (1.6 ml), 6N NaOH solution (0.8 ml), 50% H₂O₂ (0.6 ml). Thereaction mixture was heated at 50° C. for 2 hr diluted with 5%methanol/DCM and filtered. The filtrate was concentrated under reducedpressure and the crude product purified by flash column chromatographyby elution with ethyl acetate/methanol (99:1) to provide the titlecompound as a colourless oil (170 mg; 39%). ¹H NMR (400 MHz, DMSO-d6)3.72 (s, 3H), 3.66 (t, 2H), 3.41 (m, 4H), 2.64 (t, 2H), 2.17 (s, 3H),1.81 (m, 4H).

4-{[4-(2-chloroethyl)-1,5-dimethyl-1H-pyrazol-3-yl]carbonyl}morpholine

Step 1

A solution of 4-bromo-1,5-dimethyl-1H-pyrazole-3-carboxylic acid (1.0 g,4.6 mmol) in dry THF (10 ml) was treated with triethylamine (1.27 mL,9.1 mmol) and HATU (2.08 g, 5.5 mmol), followed by morpholine (470 μL,5.5 mmol). The reaction mixture was stirred at room temperatureovernight, diluted with DCM and washed with saturated sodiumbicarbonate, water and brine, dried over Na₂SO₄, concentrated underreduced pressure and the crude product purified by flash columnchromatography by elution with dichloromethane/methanol (97:3) toprovide 4-bromo-1,5-dimethyl-3-[(morpholin-4-yl)carbonyl]-1H-pyrazole(1.2 g, 91%). ¹H NMR (400 MHz, CDCl₃) 3.81 (s, 3H), 3.76 (m, 4H), 3.68(m, 2H), 3.60 (m, 2H), 2.26 (s, 3H).

Step 2

A solution of 4-bromo-1,5-dimethyl-3-[(morpholin-4-yl)carbonyl]-1H-pyrazole (500 mg, 1.7 mmol)in dry DMF (5 ml) was treated with tributylvinylstannane (1.0 mL, 3.5mmol). The mixture was purged with argon for 15 min before addition oftetrakis(triphenylphosphine) palladium(0) (100 mg, 0.087 mmol). Thereaction was heated to 110° C. overnight, diluted with ethyl acetate andwashed with potassium fluoride solution, water and brine, dried overNa₂SO₄, concentrated under reduced pressure and the crude productpurified by flash column chromatography by gradient elution withdichloromethane/methanol (96:4) to provide4-[(4-ethenyl-1,5-dimethyl-1H-pyrazol-3-yl)carbonyl]morpholine (200 mg,49%). ¹H NMR (400 MHz, DMSO-d₆) 6.56 (dd, 1H), 5.27 (dd, 1H), 5.10 (dd,1H), 3.73 (s, 3H), 3.61 (m, 4H), 3.50 (m, 2H), 3.40 (m, 2H), 2.27 (s,3H).

Step 3

A solution of4-[(4-ethenyl-1,5-dimethyl-1H-pyrazol-3-yl)carbonyl]morpholine (500 mg,2.1 mmol) in dioxane (30 ml) was treated with a solution of 9-BBN (0.5Min THF, 13 ml, 6.5 mmol) under a nitrogen atmosphere. The reaction washeated to 100° C. overnight. The mixture was re-cooled to 0° C., and wastreated with ethanol (1.0 ml), 6N NaOH solution (0.5 ml), 50% H₂O₂ (1.0ml). The reaction mixture was heated at 50° C. for 2 hr diluted withmethanol and concentrated under reduced pressure. The crude productpurified by flash column chromatography by elution with ethylacetate/methanol (95:5) to provide the title compound2-{1,5-dimethyl-3-[(morpholin-4-yl)carbonyl]-1H-pyrazol-4-yl}ethan-1-ol(200 mg, 37%). ¹H NMR (400 MHz, DMSO-d₆) 4.58 (t, 2H), 3.71 (s, 3H),3.65-3.50 (m, 8H), 3.40 (t, 3H), 2.56 (t, 2H), 2.17 (s, 3H).

Step 4

A solution of2-{1,5-dimethyl-3-[(morpholin-4-yl)carbonyl]-1H-pyrazol-4-yl}ethan-1-olin (150 mg, 0.59 mmol) in DCM (5 mL) was treated with thionyl chloride(0.6 mL) at 0° C. The reaction mixture was heated to reflux for 20 min.The reaction mixture was cooled to RT and concentrated under reducedpressure to afford desired product4-{[4-(2-chloroethyl)-1,5-dimethyl-1H-pyrazol-3-yl]carbonyl}morpholine(160 mg, 93%). ¹H NMR (400 MHz, DMSO-d₆) 3.80-3.60 (m, 13H) 2.88 (t,2H), 2.21 (s, 3H).

2-[1,5-dimethyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]ethan-1-ol

Step 1

A solution of 4-bromo-5-dimethyl-3-(trifluoromethyl)-1H-pyrazole (4.2 g,18.3 mmol) in acetone (50 mL) was treated with K₂CO₃ (5.07 g, 36.7 mmol)and iodomethane (2.28 mL, 36.7 mmol) at rt and the reaction mixture wasstirred at rt for 16 hr. The reaction mixture was then diluted withethyl acetate, washed with water and brine, dried over Na₂SO₄ andevaporated under reduced pressure. The crude product was purified bycolumn chromatography eluting with ethyl acetate/hexane (15:85) to give4-bromo-1,5-dimethyl-3-(trifluoromethyl)-1H-pyrazole (2.7 g, 61%). ¹HNMR (400 MHz, DMSO-d₆) δ 3.85 (s, 3H), 2.28 (s, 3H).

Step 2

A solution of 4-bromo-1,5-dimethyl-3-(trifluoromethyl)-1H-pyrazole (250mg, 1 mmol) in THE (5 mL) was treated with n-BuLi solution (2.4M inhexane, 0.51 mL, 1.2 mmol), dropwise at −78° C. and stirred at −78° C.for 30 min. DMF (0.159 mL) was added at −78° C. and stirred at sametemperature for 30 min. The reaction was then allowed to stir at 0° C.for 2 h. The reaction mixture was quenched with NH₄Cl solution andextracted with EtOAc. The organic layer was washed with brine, driedover Na₂SO₄ and concentrated under reduced pressure to give1,5-dimethyl-3-(trifluoromethyl)-1H-pyrazole-4-carbaldehyde (197 mg,99%). ¹H NMR (400 MHz, DMSO-d₆) δ 9.91 (s, 1H), 4.01 (s, 3H), 2.57 (s,3H).

Step 3

A solution of1,5-dimethyl-3-(trifluoromethyl)-1H-pyrazole-4-carbaldehyde (800 mg, 4.2mmol) in methanol (10 mL) was cooled at 0° C. before addition of solidNaBH₄ (315 mg, 8.3 mmol). The reaction mixture was stirred at 0° C. for2 hr, diluted with DCM, and washed with sat. NaHCO₃, water and brine,dried over Na₂SO₄, and concentrated to give[1,5-dimethyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]methanol (700 mg,87%). ¹H NMR (400 MHz, DMSO-d₆) δ 4.86 (t, 1H), 4.33 (d, 2H), 3.78 (s,3H), 2.27 (s, 3H).

Step 4

A solution of [1,5-dimethyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]methanol(850 mg, 4.4 mmol) in DCM (15 mL) was cooled at 0° C. before dropwiseaddition of trimethylamine (1.28 mL, 9.2 mmol) and mesylchloride (0.712mL, 9.2 mmol). The reaction mixture was stirred at rt for 6 hr, dilutedwith DCM, then washed with sat. NaHCO₃, water and brine, dried overNa₂SO₄ and evaporated to give[1,5-dimethyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]methylmethanesulfonate (1.0 g, 84%). ¹H NMR (400 MHz, DMSO-d₆) δ 4.70 (s, 2H),3.60 (s, 3H), 2.31 (s, 3H).

Step 5

A solution of [1,5-dimethyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]methylmethanesulfonate (1.0 g, 3.7 mmol) in DMF was treated with sodiumcyanide (0.54 g, 11 mmol) and the reaction mixture was heated at 100° C.for 16 hr. The reaction mixture was diluted with ethyl acetate, washedwith water and brine, dried over Na₂SO₄ and evaporated under reducedpressure to give2-[1,5-dimethyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]acetonitrile (740mg, 99%). ¹H NMR (400 MHz, DMSO-d₆) δ 3.87 (s, 2H), 3.80 (s, 3H), 2.31(s, 3H).

Step 6

A solution of2-[1,5-dimethyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]acetonitrile (740mg, 3.6 mmol) in methanol (10 mL) was treated with a solution of 4M HClin dioxane (4M, 5 mL) at rt. The reaction mixture was heated at 80° C.for 3 hours, cooled and evaporated under reduced pressure. The crudematerial was dissolved in ethyl acetate, washed with NaHCO₃ solution,water and brine, then dried over Na₂SO₄ and concentrated to give methyl2-[1,5-dimethyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]acetate (856 mg,93%). ¹H NMR (400 MHz, DMSO-d₆) δ 3.98 (s, 3H), 3.59 (s, 3H), 3.56 (s,2H), 2.19 (s, 3H).

Step 7

A solution of LiAlH₄ (255 mg, 6.8 mmol) in THF (5 mL) was cooled at 0°C., before dropwise addition of methyl2-[1,5-dimethyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]acetate (800 mg, 3.4mmol) in THF (5 mL). Then the reaction mixture was stirred at 0° C. for2 hours. The reaction mixture was cooled at 0° C. Excess of LAH wasquenched with Na₂SO₄ solution. The mixture was stirred at rt for 30 minand was filtered through celite bed, which was washed with ethylacetate. Then the ethyl acetate solution was taken dried over Na₂SO₄ andevaporated under reduced pressure. The crude product was purified bycolumn chromatography silica eluting with EtOAc/hexane (1:1) to give thetitle compound as an oil (350 mg, 50%). ¹H NMR (400 MHz, DMSO-d₆) δ 4.25(t, 2H), 3.76 (s, 3H), 3.40 (q, 2H), 2.56 (t, 2H), 2.21 (s, 3H).

4-[2-(2-bromo-5-fluorophenoxy)ethyl]-1,3,5-trimethyl-1H-pyrazole Step 1

A solution of 2-bromo-5-fluorophenol (5.0 g, 26 mmol) in dichloromethane(100 mL) was cooled to 0° C. then treated with triethylamine (7.6 mL, 55mmol) followed by methanesulfonyl chloride (4.25 mL, 55 mmol). Thereaction mixture was allowed to warm to room temperature and was stirredfor 18 hours before being quenched with sodium bicarbonate solution (2M,20 ml). Ethyl acetate was added and the layers were separated. Theorganic phase was washed with water and brine, then dried (Na₂SO₄) andconcentrated under reduced pressure to give the product,2-bromo-5-fluorophenyl methanesulfonate (7 g, yield: 99%). ¹H NMR (400MHz, DMSO-d6) δ 7.84 (dd, 1H), 7.53 (dd, 1H), 7.26 (td, 1H), 3.56 (s,3H),

Step 2

According to the general method for mesyl transfer (method B), asolution of 2-bromo-5-fluorophenyl methanesulfonate (1.45 g, 5.4 mmol)in dry DMF (25 ml) was treated with a solution of2-(1,3,5-trimethyl-1H-pyrazol-4-yl)ethanol (1.49 g, 9.7 mmol) in dry DMF(25 mL), followed by solid cesium carbonate (2.46 g, 7.5 mmol). Thereaction mixture was heated to 90° C. overnight. The reaction mixturewas partitioned between ethyl acetate (50 ml) and water (10 ml). Theorganic phase was washed with water, dried over Na₂SO₄, concentratedunder reduced pressure and the crude product purified by flash columnchromatography by elution with ethyl acetate/hexane (1:4) to provide thetitle compound (800 mg; 45%) ¹H NMR (400 MHz, DMSO-d6) δ 7.57 (dd, 1H),7.02 (dd, 2H), 6.74 (td, 1H), 4.03 (t, 2H), 3.60 (s, 3H), 2.75 (t, 2H),2.17 (s, 3H), 2.10 (s, 3H).

4-([4-(2-chloroethyl)-1,5-dimethyl-1H-pyrazol-3-yl]carbonyl)morpholine

Step 1

A solution of 4-bromo-1,5-dimethyl-1H-pyrazole-carbonitrile (8.0 g, 40mmol) in dry DMF (40 mL) was treated with tributylvinylstannane (23.4mL, 80 mmol). The mixture was purged with argon for 15 min beforeaddition of tetrakis(triphenylphosphine) palladium(0) (2.3 g, 2 mmol).The reaction was heated to 110° C. overnight, diluted with ethyl acetateand washed with potassium fluoride solution, water and brine, dried overNa₂SO₄, concentrated under reduced pressure. The crude product waspurified by flash column chromatography by elution withethylacetate/hexane (20:80) to provide4-ethenyl-1,5-dimethyl-1H-pyrazole-3-carbonitrile (4.0 g, 68%). ¹H NMR(400 MHz, CDCl₃) 6.45 (dd; 1H), 5.80 (dd, 1H), 5.34 (dd, 1H), 3.82 (s,3H), 2.29 (s, 3H).

Step 2

A solution of 4-ethenyl-1,5-dimethyl-1H-pyrazole-3-carbonitrile (1.2 g,8.2 mmol) in dioxane (5 mL) was treated with a solution of 9-BBN (0.5Min THF, 32 ml, 16 mmol) under a nitrogen atmosphere. The reaction washeated to 100° C. overnight. The mixture was re-cooled to 0° C., and wastreated with ethanol (4.8 mL), NaOH solution (6M, 2.4 mL), H₂O₂ (50%solution, 3.6 mL). The reaction mixture was heated at RT for 2 hrdiluted with DCM/methanol (95:5), dried over sodium sulphate andconcentrated under reduced pressure. The crude product purified by flashcolumn chromatography by elution with DCM/methanol (98:2) to provide thetitle compound4-(2-hydroxyethyl)-1,5-dimethyl-1H-pyrazole-3-carbonitrile (500 mg,37%). ¹H NMR (400 MHz, CDCl₃) 3.81 (s, 3H), 3.78 (q, 2H), 2.74 (t, 2H),2.55 (s, 3H), 1.86 (t, 1H).

Step 3

A solution of 4-(2-hydroxyethyl)-1,5-dimethyl-1H-pyrazole-3-carbonitrile(1.0 g, 6.1 mmol) in methanol (12 mL) was treated with a solution of HClin dioxane (4M, 12 mL). The reaction mixture was stirred at 80° C. for 5hr and evaporated under reduced pressure. The crude product was basifiedwith sat. NaHCO₃ solution and diluted with EtOAc, washed with water,brine, dried over sodium sulfate and evaporated under reduced pressureto give methyl 4-(2-hydroxyethyl)-1,5-dimethyl-1H-pyrazole-3-carboxylate(1.1 g, 92%). ¹H NMR (400 MHz, CDCl₃) 3.90 (s, 3H), 3.84 (s, 3H), 3.77(q, 2H), 2.93 (t, 2H), 2.23 (s, 3H), 2.07 (t, 1H).

Step 4

A solution of methyl4-(2-hydroxyethyl)-1,5-dimethyl-1H-pyrazole-3-carboxylate (100 mg, 0.5mmol) in DCM (1.5 mL) was treated with thionyl chloride (0.5 mL) at 0°C. The reaction mixture was heated to reflux for 1 hr. The reactionmixture was cooled to RT and concentrated under reduced pressure toafford desired product, methyl4-(2-chloroethyl)-1,5-dimethyl-1H-pyrazole-3-carboxylate (100 mg, 91%).¹H NMR (400 MHz, DMSO-d₆) 3.76 (s, 3H), 3.74 (s, 3H), 3.41 (t, 2H), 2.73(t, 2H), 2.20 (s, 3H).

Preparation of Intermediates 1-29 Intermediate 1

2-(3-((Dimethylamino)methyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)phenylmethanesulfonate Step 1

A solution of5-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-3-carbaldehyde (1.78 g,5 mmol) was dissolved in dioxane (20 ml) and treated with2-hydroxybenzene boronic acid (690 mg, 5 mmol) andtetrakis(triphenylphosphine) palladium(0) (100 mg), followed by asolution of potassium phosphate (1.59 g, 7.5 mmol) in water (5 ml). Thereaction mixture was heated under reflux for 1 hr, cooled to roomtemperature and evaporated under reduced pressure. The residue waspartitioned between ethyl acetate (20 ml) and saturated sodiumbicarbonate solution (20 ml). The organic phase was dried over Na₂SO₄,concentrated under reduced pressure and the crude product purified byflash column chromatography by elution with DCM/EtOAc (100:0, then 95:5)to give5-(2-hydroxyphenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-3-carbaldehydeas a pale yellow solid (1.15 g, 71%) mp 162-163° C. ¹H NMR (400 MHz,Chloroform-d) δ 10.29 (s, 1H), 8.44 (d, J=1.9 Hz, 1H), 7.81 (d, J=0.8.8Hz, 1H), 7.64 (dd, J=8.6, 1.7 Hz, 1H), 7.35-7.28 (m, 2H), 7.08-7.03 (m,1H), 7.01 (d, J=8.0 Hz, 1H), 5.90 (dd, J=8.9, 2.7 Hz, 1H), 5.13 (s, 1H),4.13-4.00 (m, 1H), 3.91-3.76 (m, 1H), 2.62 (m, 1H), 2.31-2.13 (m, 2H),1.94-1.70 (m, 3H).

Step 2

A solution of5-(2-hydroxyphenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-3-carbaldehyde(800 mg, 2.4 mmol) in THF (20 ml) was cooled to 0° C. then treated withtriethylamine (370 μl. 4.8 mmol) followed by methanesulfonyl chloride(670 μl, 4.8 mmol). The reaction mixture was allowed to warm to roomtemperature and was stirred for 18 hours before being quenched withsaturated sodium bicarbonate solution (10 ml). EtOAc (50 ml) was addedand the layers were separated. The aqueous phase was further extractedwith EtOAc (20 ml) and the combined organic extracts were dried (Na₂SO₄)and concentrated under reduced pressure. The crude product was purifiedby column chromatography by elution with DCM/EtOAc (97:3) to give2-(3-formyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)phenylmethanesulfonate as a colourless oil (830 mg, 92%). ¹H NMR (400 MHz,Chloroform-d) δ 10.30 (s, 1H), 8.46 (d, J=1.5 Hz, 1H), 7.80 (d, J=8.8Hz, 1H), 7.75 (dd, J=8.8, 1.7 Hz, 1H), 7.60-7.51 (m, 2H), 7.50-7.43 (m,2H), 5.91 (dd, J=9.0, 2.7 Hz, 1H), 4.13-4.05 (m, 1H), 3.85 (ddd, J=12.7,9.6, 3.3 Hz, 1H), 2.66-2.59 (m, 4H), 2.33-2.13 (m, 2H), 1.96-1.72 (m,3H).

Step 3

A solution of2-(3-formyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)phenylmethanesulfonate (830 mg, 2.2 mmol) in DCE (20 ml) was treated with asolution of dimethylamine in THF (2M, 3.3 ml, 6.6 mmol), followed byglacial acetic acid (750 μl, 13.2 mmol). The solution was stirred atroom temperature for 10 mins before addition of solid sodiumtriacetoxyborohydride (1.40 g, 6.6 mmol). The reaction mixture wasstirred at room temperature for 18 hours before being quenched withsodium carbonate solution (2M, 20 ml). DCM (20 ml) was added and thelayers were separated. The aqueous phase was further extracted with DCM(10 ml) and the combined organic extracts were dried (Na₂SO₄) andconcentrated under reduced pressure. The crude product was purified bycolumn chromatography by elution with EtOAc/diethylamine (95:5) to givethe title compound as a colourless oil (650 mg, 69%). ¹H NMR (400 MHz,Chloroform-d) δ 8.03 (d, J=1.5 Hz, 1H), 7.66 (d, J=8.6 Hz, 1H), 7.58(dd, J=8.6, 1.6 Hz, 1H), 7.52 (m, 2H), 7.42 (m 2H), 5.72 (dd, J=9.9, 2.5Hz, 1H), 4.21-4.07 (m, 1H), 3.85 (d, J=2.4 Hz, 2H), 3.79 (td, J=11.2,10.7, 2.5 Hz, 1H), 2.64-2.58 (m, 1H), 2.56 (s, 3H), 2.32 (s, 6H),2.22-2.13 (m, 1H), 2.08 (m 1H), 1.85-1.75 (m, 2H), 1.73-1.64 (m, 1H).

Intermediate 2

2-(3-((dimethylamino)methyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)-5-fluorophenylmethanesulfonate

Step 1

A solution of5-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-3-carbaldehyde (1.60 g,4.5 mmol) was dissolved in dioxane (20 ml) and treated with4-fluoro-2-hydroxybenzene boronic acid (697 mg, 4.5 mmol) andtetrakis(triphenylphosphine) palladium(0) (100 mg), followed by asolution of potassium phosphate (1.43 g, 6.7 mmol) in water (5 ml). Thereaction mixture was heated under reflux for 2 hr, cooled to roomtemperature and evaporated under reduced pressure. The residue waspartitioned between ethyl acetate (20 ml) and saturated sodiumbicarbonate solution (20 ml). The organic phase was dried over Na₂SO₄,concentrated under reduced pressure and the crude product purified byflash column chromatography by elution with DCM/EtOAc (100:0, then 95:5)to give5-(4-fluoro-2-hydroxyphenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-3-carbaldehydeas a colourless solid (1.15 g, 75%). mp 171-173° C. ¹H NMR (400 MHz,Chloroform-d) δ 10.28 (s, 1H), 8.39 (d, J=2.1 Hz, 1H), 7.82 (d, J=8.7Hz, 1H), 7.56 (dd, J=8.8, 1.9 Hz, 1H), 7.25 (dd, J=9.2, 6.5 Hz, 1H),6.80-6.72 (m, 2H), 5.94-5.87 (m, 1H), 5.34 (s, 1H), 4.11-3.98 (m, 1H),3.83 (ddd, J=1H), 2.69-2.52 (m, 1H), 2.30-2.12 (m, 2H), 1.94-1.71 (m,3H).

Step 2

A solution of5-(4-fluoro-2-hydroxyphenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-3-carbaldehyde(1.15 g, 3.3 mmol) in THF (20 ml) was cooled to 0° C. then treated withtriethylamine (520p. 6.6 mmol) followed by methanesulfonyl chloride (940μl, 6.6 mmol). The reaction mixture was allowed to warm to roomtemperature and was stirred for 18 hours before being quenched withsaturated sodium bicarbonate solution (10 ml). EtOAc (50 ml) was addedand the layers were separated. The aqueous phase was further extractedwith EtOAc (20 ml) and the combined organic extracts were dried (Na₂SO₄)and concentrated under reduced pressure to give5-fluoro-2-(3-formyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)phenylmethanesulfonate as a colourless oil (1.20 g, −100%). ¹H NMR (400 MHz,Chloroform-d) δ 10.28 (s, 1H), 8.40 (d, J=1.6 Hz, 1H), 7.79 (d, J=8.7Hz, 1H), 7.67 (dd, J=8.6, 1.6 Hz, 1H), 7.52 (dd, J=8.6, 6.2 Hz, 1H),7.31 (dd, J=8.9, 2.6 Hz, 1H), 7.17 (td, J=8.2, 2.6 Hz, 1H), 5.89 (dd,J=9.1, 2.6 Hz, 1H), 4.07 (dd, J=8.8, 5.3 Hz, 1H), 3.83 (ddd, J=12.6,9.6, 3.3 Hz, 1H), 2.67 (s, 3H), 2.60 (dtd, J=13.3, 9.3, 5.4 Hz, 1H),2.31-2.11 (m, 2H), 1.93-1.69 (m, 3H).

Step 3

A solution of5-fluoro-2-(3-formyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)phenylmethanesulfonate (1.20 g, 3.3 mmol) in DCE (20 ml) was treated with asolution of dimethylamine in THF (2M, 5.0 ml, 9.9 mmol), followed byglacial acetic acid (1200 μl, 19.8 mmol). The solution was stirred atroom temperature for 10 mins before addition of solid sodiumtriacetoxyborohydride (2.10 g, 9.9 mmol). The reaction mixture wasstirred at room temperature for 18 hours before being quenched withsodium carbonate solution (2M, 20 ml). DCM (20 ml) was added and thelayers were separated. The aqueous phase was further extracted with DCM(10 ml) and the combined organic extracts were dried (Na₂SO₄) andconcentrated under reduced pressure. The crude product was purified bycolumn chromatography by elution with EtOAc/diethylamine (95:5), thentriturated with cyclohexane to give the title compound as a colourlesssolid (880 mg, 60%). mp 148-150° C. ¹H NMR (400 MHz, Chloroform-d) δ8.00 (d, J=1.3 Hz, 1H), 7.67 (d, J=8.6 Hz, 1H), 7.56-7.51 (m, 1H),7.52-7.46 (m, 1H), 7.34-7.27 (m, 1H), 7.16 (td, J=8.2, 2.6 Hz, 1H), 5.73(dd, J=9.9, 2.6 Hz, 1H), 4.19-4.08 (m, 1H), 3.86 (d, J=2.6 Hz, 2H), 3.80(td, J=10.9, 2.5 Hz, 1H), 2.63 (s, 3H), 2.60-2.55 (m, 1H), 2.33 (s, 6H),2.19 (dd, J=9.4, 4.6 Hz, 1H), 2.15-2.05 (m, 1H), 1.87-1.76 (m, 2H),1.75-1.64 (m, 1H).

Intermediate 3

3-(3-((Dimethylamino)methyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)phenylmethanesulfonate Step 1

A solution of5-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-3-carbaldehyde (1.60 g,4.5 mmol) was dissolved in dioxane (20 ml) and treated with3-hydroxybenzene boronic acid (690 mg, 5 mmol) andtetrakis(triphenylphosphine) palladium(0) (100 mg), followed by asolution of potassium phosphate (1.43 g, 6.7 mmol) in water (5 ml). Thereaction mixture was heated under reflux for 2 hr, cooled to roomtemperature and evaporated under reduced pressure. The residue waspartitioned between ethyl acetate (20 ml) and saturated sodiumbicarbonate solution (20 ml). The organic phase was dried over Na₂SO₄,concentrated under reduced pressure and the crude product purified byflash column chromatography by elution with DCM/EtOAc (100:0, then 95:5)to give5-(3-hydroxyphenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-3-carbaldehydeas a pale yellow solid (910 mg, 62%). ¹H NMR (400 MHz, Chloroform-d) δ10.29 (s, 1H), 8.51 (s, 1H), 7.74 (s, 2H), 7.35 (t, J=7.7 Hz, 1H), 7.25(d, J=7.8 Hz, 1H), 7.16 (d, J=2.1 Hz, 1H), 6.87 (dd, J=8.1, 2.3 Hz, 1H),5.89 (dd, J=9.1, 2.7 Hz, 1H), 5.04 (s, 1H), 4.05 (dt, J=10.9, 3.8 Hz,1H), 3.83 (dt, J=11.7, 5.8 Hz, 1H), 2.61 (td, J=13.2, 11.8, 7.1 Hz, 1H),2.30-2.11 (m, 2H), 1.92-1.68 (m, 3H).

Step 2

A solution of5-(3-hydroxyphenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-3-carbaldehyde(900 mg, 2.8 mmol) in THF (20 ml) was cooled to 0° C. then treated withtriethylamine (433 μl. 5.6 mmol) followed by methanesulfonyl chloride(780 μl, 5.6 mmol). The reaction mixture was allowed to warm to roomtemperature and was stirred for 18 hours before being quenched withsaturated sodium bicarbonate solution (10 ml). EtOAc (50 ml) was addedand the layers were separated. The aqueous phase was further extractedwith EtOAc (20 ml) and the combined organic extracts were dried (Na₂SO₄)and concentrated under reduced pressure to give3-(3-formyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)phenylmethanesulfonate as a colourless oil (1.0 g, −100%). ¹H NMR (400 MHz,Chloroform-d) δ 10.30 (s, 1H), 8.52 (d, J=1.6 Hz, 1H), 7.78 (d, J=8.8Hz, 1H), 7.72 (dd, J=8.9, 1.5 Hz, 1H), 7.66 (dt, J=7.8, 1.2 Hz, 1H),7.58 (t, J=2.1 Hz, 1H), 7.53 (t, J=7.9 Hz, 1H), 7.32 (dd, J=7.9, 2.4 Hz,1H), 5.90 (dd, J=8.9, 2.7 Hz, 1H), 4.05 (dt, J=11.4, 3.9 Hz, 1H),3.92-3.70 (m, 1H), 3.22 (s, 3H), 2.70-2.51 (m, 1H), 2.30-2.12 (m, 2H),1.95-1.71 (m, 3H).

Step 3

A solution of3-(3-formyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)phenylmethanesulfonate (1.0 g, 2.8 mmol) in DCE (20 ml) was treated with asolution of dimethylamine in THF (2M, 4.2 ml, 8.4 mmol), followed byglacial acetic acid (1000 1, 16.8 mmol). The solution was stirred atroom temperature for 10 mins before addition of solid sodiumtriacetoxyborohydride (1.78 g, 8.4 mmol). The reaction mixture wasstirred at room temperature for 18 hours before being quenched withsodium carbonate solution (2M, 20 ml). DCM (20 ml) was added and thelayers were separated. The aqueous phase was further extracted with DCM(10 ml) and the combined organic extracts were dried (Na₂SO₄) andconcentrated under reduced pressure. The crude product was purified bycolumn chromatography by elution with EtOAc/diethylamine (95:5) to givethe title compound as a colourless oil (710 mg, 59%). ¹H NMR (400 MHz,Chloroform-d) δ 8.05 (d, J=1.6 Hz, 1H), 7.66 (d, J=8.7 Hz, 1H),7.67-7.58 (m, 2H), 7.57 (t, J=2.1 Hz, 1H), 7.51 (t, J=7.9 Hz, 1H), 7.29(dd, J=8.1, 2.3 Hz, 1H), 5.73 (dd, J=9.7, 2.7 Hz, 1H), 4.16-4.05 (m,1H), 3.90 (d, J=3.0 Hz, 2H), 3.79 (td, J=11.0, 3.0 Hz, 1H), 3.22 (s,3H), 2.69-2.51 (m, 1H), 2.37 (s, 6H), 2.18 (td, J=6.2, 5.3, 2.4 Hz, 1H),2.09 (dt, J=12.3, 3.3 Hz, 1H), 1.87-1.76 (m, 2H), 1.75-1.61 (m, 1H).

Intermediate 4

2-(3-((dimethylamino)methyl)-1-methyl-1H-indazol-5-yl)-5-fluorophenylmethanesulfonate Step 1

A suspension of 5-iodo-N-methoxy-N-methyl-1H-indazole-3-carboxamide (1.0g, 3.0 mmol) in DCM (20 ml) was treated with a catalytic quantity oftetrabutylammomium bromide and a 50% solution of potassium hydroxide inwater (20 ml). The biphasic mixture was cooled to 0° C. before dropwiseaddition of iodomethane (204 μl, 4.4 mmol). The mixture was stirredvigorously and allowed to warm to room temperature overnight. The layerswere separated and the aqueous layer re-extracted with DCM (10 ml). Theorganic phase was dried over Na₂SO₄, concentrated under reduced pressureand the crude product purified by flash column chromatography by elutionwith DCM/EtOAc (85:15, then 80:20) to separate the product regioisomers.The major product was eluted first and was assigned as5-iodo-N-methoxy-N, 1dimethyl-1H-indazole-3-carboxamide by NMR (800 mg,77%). mp 128-130° C. ¹H NMR (400 MHz, Chloroform-d) δ 8.64 (d, J=1.7 Hz,1H), 7.68 (dd, J=8.8, 1.5 Hz, 1H), 7.22 (d, J=8.8 Hz, 1H), 4.13 (s, 3H),3.86 (s, 3H), 3.54 (s, 3H). Fractions containing the minor product werere-chromatographed to give a product that was assigned as5-iodo-N-methoxy-N,2-dimethyl-2H-indazole-3-carboxamide by NMR.δ_(H)/ppm ¹H NMR (400 MHz, Chloroform-d) δ 8.10 (d, J=1.7 Hz, 1H), 7.49(dd, J=9.1, 1.6 Hz, 1H), 7.45 (d, J=9.0 Hz, 1H), 4.27 (s, 3H), 3.49 (s,3H), 3.42 (s, 3H).

Step 2

A solution of 5-iodo-N-methoxy-N, 1-dimethyl-1H-indazole-3-carboxamide(800 mg, 2.3 mmol) in THF (5 ml) was cooled to 0° C. before dropwiseaddition of a solution of lithium aluminium hydride in THF (2M, 0.35 ml,0.7 mmol). The reaction mixture was stirred for 30 min then quenched byaddition of EtOAc (1 ml), allowed to warm to room temperature thenpartitioned between EtOAc (20 ml) and potassium hydrogen sulphatesolution (1M, 20 ml). The organic phase was dried over Na₂SO₄ andconcentrated under reduced pressure to give5-iodo-1-methyl-1H-indazole-3-carbaldehyde as a pale yellow solid (600mg, 91%) mp 134-136° C. ¹H NMR (400 MHz, Chloroform-d) δ 10.14 (s, 1H),8.61 (d, J=1.5 Hz, 1H), 7.68 (dd, J=8.9, 1.7 Hz, 1H), 7.21 (d, J=8.9 Hz,1H), 4.15 (s, 3H).

Step 3

A solution of 5-iodo-1-methyl-1H-indazole-3-carbaldehyde (500 mg, 1.7mmol) was dissolved in dioxane (5 ml) and treated with4-fluoro-2-hydroxybenzene boronic acid (360 mg, 2.2 mmol) andtetrakis(triphenylphosphine) palladium(0) (20 mg), followed by asolution of potassium phosphate (560 mg, 2.6 mmol) in water (1 ml). Thereaction mixture was heated under reflux for 2 hr, cooled to roomtemperature and evaporated under reduced pressure. The residue waspartitioned between ethyl acetate (20 ml) and saturated sodiumbicarbonate solution (20 ml). The organic phase was dried over Na₂SO₄,concentrated under reduced pressure and the crude product purified byflash column chromatography by elution with DCM/EtOAc (100:0, then 95:5)to give 5-(4-fluoro-2-hydroxyphenyl)-1methyl-1H-indazole-3-carbaldehydeas a colourless solid (450 mg, 95%). mp 212-214° C. ¹H NMR (400 MHz,Methanol-d4) δ 10.15 (s, 1H), 8.30 (d, J=1.3 Hz, 1H), 7.73 (d, J=1.5 Hz,1H), 7.69 (s, 1H), 7.32 (dd, J=9.2, 6.7 Hz, 1H), 6.74-6.64 (m, 2H), 4.62(s, 1H), 4.24 (s, 3H).

Step 4

A solution of5-(4-fluoro-2-hydroxyphenyl)-1-methyl-1H-indazole-3-carbaldehyde (440mg, 1.6 mmol) in THF (10 ml) was cooled to 0° C. then treated withtriethylamine (250 μl. 3.2 mmol) followed by methanesulfonyl chloride(450 μl, 3.2 mmol). The reaction mixture was allowed to warm to roomtemperature and was stirred for 18 hours before being quenched withsaturated sodium bicarbonate solution (10 ml). EtOAc (50 ml) was addedand the layers were separated. The aqueous phase was further extractedwith EtOAc (20 ml) and the combined organic extracts were dried (Na₂SO₄)and concentrated under reduced pressure to give5-fluoro-2-(3-formyl-1-methyl-1H-indazol-5-yl)phenyl methanesulfonate asa colourless solid (525 mg, 94%) mp 181-183° C. ¹H NMR (400 MHz,Chloroform-d) δ 10.26 (s, 1H), 8.46-8.37 (m, 1H), 7.70 (dd, J=8.8, 1.5Hz, 1H), 7.59 (d, J=8.7 Hz, 1H), 7.53 (dd, J=8.7, 6.3 Hz, 1H), 7.31 (dd,J=8.8, 2.5 Hz, 1H), 7.18 (td, J=8.2, 2.6 Hz, 1H), 4.26 (s, 3H), 2.69 (s,3H).

Step 5

A solution of 5-fluoro-2-(3-formyl-1-methyl-1H-indazol-5-yl)phenylmethanesulfonate (520 mg, 1.6 mmol) in DCE (5 ml) was treated with asolution of dimethylamine in THF (2M, 2.4 ml, 4.8 mmol), followed byglacial acetic acid (580 μl, 9.6 mmol). The solution was stirred at roomtemperature for 10 mins before addition of solid sodiumtriacetoxyborohydride (1.10 g, 4.8 mmol). The reaction mixture wasstirred at room temperature for 18 hours before being quenched withsodium carbonate solution (2M, 20 ml). DCM (20 ml) was added and thelayers were separated. The aqueous phase was further extracted with DCM(10 ml) and the combined organic extracts were dried (Na₂SO₄) andconcentrated under reduced pressure. The crude product was purified bycolumn chromatography by elution with EtOAc/diethylamine (95:5), thentriturated with cyclohexane to give the title compound as a colourlesssolid (350 mg, 58%). Mp 105-107° C. ¹H NMR (400 MHz, Chloroform-d) δ7.95 (d, J=1.4 Hz, 1H), 7.53 (dd, J=6.9, 1.9 Hz, 1H), 7.52-7.48 (m, 1H),7.44 (d, J=8.7 Hz, 1H), 7.28 (dd, J=8.8, 2.8 Hz, 1H), 7.15 (td, J=8.1,2.6 Hz, 1H), 4.09 (s, 3H), 3.83 (s, 2H), 2.60 (s, 3H), 2.32 (s, 6H).

Intermediate 5

2-(3-((dimethylamino)methyl)-1-methyl-1H-indazol-5-yl)-5-fluorophenol

A solution of5-(4-fluoro-2-hydroxyphenyl)-1-methyl-1H-indazole-3-carbaldehyde (forpreparation see Intermediate 4, step 3) (100 mg, 0.4 mmol) in THF (3 ml)was treated with a solution of dimethylamine in THF (2M, 0.6 ml, 1.2mmol), followed by glacial acetic acid (145 μl, 2.4 mmol). The solutionwas stirred at room temperature for 10 mins before addition of solidsodium triacetoxyborohydride (250 mg, 1.2 mmol) and DCE (2 ml). Thereaction mixture was stirred at room temperature for 18 hours beforebeing quenched with sodium carbonate solution (2M, 20 ml). DCM (20 ml)was added and the layers were separated. The aqueous phase was furtherextracted with DCM (10 ml) and the combined organic extracts were dried(Na₂SO₄) and concentrated under reduced pressure. The crude product waspurified by column chromatography by elution with EtOAc/diethylamine(95:5), to give the title compound as a colourless foam (81 mg, 68%). ¹HNMR (400 MHz, Chloroform-d) δ 8.27 (s, 1H), 7.88 (d, J=1.5 Hz, 1H), 7.48(dd, J=8.7, 1.5 Hz, 1H), 7.35 (d, J=8.7 Hz, 1H), 7.11. (dd, J=8.6, 6.7Hz, 1H), 6.58 (td, J=8.4, 2.5 Hz, 1H), 6.47 (dd, J=10.5, 2.6 Hz, 1H),4.03 (s, 3H), 3.86 (s, 2H), 2.34 (s, 6H).

Intermediate 6

5-(4-fluoro-2-(2-(1,3,5-trimethyl-1H-pyrazol-4-yl)ethoxy)phenyl)-1-methyl-1H-indazole-3-carbaldehyde

A solution of5-(4-fluoro-2-hydroxyphenyl)-1-methyl-1H-indazole-3-carbaldehyde (forpreparation see Intermediate 4, step 3) (200 mg; 0.74 mmol) andtriphenylphosphine (388 mg; 1.48 mmol) in THF (4 mL) was treated with asolution of 2-(1,3,5-trimethyl-1H-pyrazol-4-yl)ethanol (288 mg, 1.48mmol) in THF (3 mL). The reaction mixture was cooled to 0° C. beforebeing treated with di-isopropyl azodicarboxylate (29 μl, 1.48 mmol). Thereaction mixture was allowed to warm to room temperature, stirredovernight and concentrated under reduced pressure. The crude product waspurified by automated column chromatography by elution with hexane/IPA(gradient 95:5 to then 30:70) to give the title compound as a colourlessoil (240 mg, 80%). ¹H NMR (400 MHz, Chloroform-d) δ 10.22 (s, 1H), 8.37(d, J=1.5 Hz, 1H), 7.57 (dd, J=8.8, 1.5 Hz, 1H), 7.46 (d, J=8.7 Hz, 1H),7.29 (dd, J=8.4, 6.8 Hz, 1H), 6.72 (td, J=8.3, 2.5 Hz, 1H), 6.67 (dd,J=11.1, 2.4 Hz, 1H), 4.21 (s, 3H), 3.94 (t, J=7.2 Hz, 2H), 3.62 (s, 3H),2.74 (t, J=7.1 Hz, 2H), 2.04 (s, 3H), 1.95 (s, 3H).

Intermediate 7

1-(5-(4-fluoro-2-(2-(4-methylthiazol-5-yl)ethoxy)phenyl)-1-methyl-1H-indazol-3-yl)ethanoneStep 1

A solution of 5-iodo-N-methoxy-N, 1-dimethyl-1H-indazole-3-carboxamide[product of intermediate 4 step 1) (400 mg, 1.15 mmol) in THF (5 ml) wascooled to 0° C. before dropwise addition of a methylmagnesium bromide inTHF/Toluene (1.4M, 2.5 ml, 1.8 mmol). The reaction mixture was stirredfor 1 hr then quenched by addition of EtOAc (1 ml), allowed to warm toroom temperature then partitioned between EtOAc (20 ml) and saturatedammonium chloride solution (10 ml). The organic phase was dried overNa₂SO₄ and concentrated under reduced pressure to give1-(5-iodo-1-methyl-1H-indazole-3-yl) ethanone as a pale yellow solid(308 mg, 86%) mp 178-180° C. ¹H NMR (400 MHz, Chloroform-d) δ 8.77 (d,J=1.5 Hz, 1H), 7.70 (dd, J=8.8, 1.5 Hz, 1H), 7.23 (d, J=8.8 Hz, 1H),4.15 (s, 3H), 2.71 (s, 3H).

Step 2

A solution of 1-(5-iodo-1-methyl-1H-indazole-3-yl) ethanone (308 mg, 1.0mmol) was dissolved in dioxane (5 ml) and treated with4-fluoro-2-hydroxybenzene boronic acid (202 mg, 1.3 mmol) andtetrakis(triphenylphosphine) palladium(0) (10 mg), followed by asolution of potassium phosphate (432 mg, 2.0 mmol) in water (1 ml). Thereaction mixture was heated under reflux for 2 hr, cooled to roomtemperature and evaporated under reduced pressure. The residue waspartitioned between ethyl acetate (20 ml) and saturated sodiumbicarbonate solution (20 ml). The organic phase was dried over Na₂SO₄,concentrated under reduced pressure and the crude product purified byflash column chromatography by elution with DCM/EtOAc (100:0, then90:10) to give1-(5-(4-fluoro-2-hydroxyphenyl)-1-methyl-1H-indazole-3-yl)ethanone as acolourless solid (277 mg, 97%). mp 228-229° C. ¹H NMR (400 MHz,Methanol-d4) δ 8.33 (d, J=1.7 Hz, 1H), 7.68 (dd, J=8.8, 1.5 Hz, 1H),7.60 (d, J=8.7 Hz, 1H), 7.35-7.23 (m, 1H), 6.71-6.62 (m, 2H), 4.18 (s,3H), 2.68 (s, 3H).

Step 3

A solution1-(5-(4-fluoro-2-hydroxyphenyl)-1-methyl-1H-indazole-3-yl)ethanone (155mg, 0.5 mmol) in dichloromethane (10 ml) was cooled to 0° C. thentreated with triethylamine (166 μl. 1.0 mmol) followed bymethanesulfonyl chloride (84 μl, 1.0 mmol). The reaction mixture wasallowed to warm to room temperature and was stirred for 18 hours beforebeing quenched with saturated sodium bicarbonate solution (10 ml).Dichloromethane (20 ml) was added and the layers were separated. Theaqueous phase was further extracted with dichloromethane (20 ml) and thecombined organic extracts were dried (Na₂SO₄) and concentrated underreduced pressure. The crude product was purified by columnchromatography by elution with dichloromethane/ethyl acetate (90:10).Fractions containing the product were combined and evaporated to give2-(3-acetyl-1-methyl-1H-indazol-5-yl)-5-fluorophenyl methanesulfonate asa pale yellow solid (105 mg, 54%), mp 167-168° C.

¹H NMR (400 MHz, Chloroform-d) 68.47 (d, J=1.4 Hz, 1H), 7.67-7.62 (m,1H), 7.57-7.50 (m, 2H), 7.31 (dd, J=8.9, 2.6 Hz, 1H), 7.17 (td, J=8.2,2.6 Hz, 1H), 4.22 (s, 3H), 2.74 (s, 3H), 2.66 (s, 3H).

Step 4

According to the general method for mesyl transfer (Method A),2-(3-acetyl-1-methyl-1H-indazol-5-yl)-5-fluorophenyl methanesulfonate(65 mg, 0.18 mmol was reacted with 2-(4-methylthiazol-5-yl)ethanol (51mg, 0.36 mmol) and sodium t-butoxide (34 mg, 0.36 mmol) in acetonitrile(0.5 ml). Purification by column chromatography by elution withdichloromethane/ethyl acetate (80:20), followed by ethylacetate/diethylamine (95:50 provided1-(5-(4-fluoro-2-(2-(4-methylthiazol-5-yl)ethoxy)phenyl)-1-methyl-1H-indazol-3-yl)ethanoneas a colourless oil (40 mg, 54%). ¹H NMR (400 MHz, Chloroform-d) δ 8.53(s, 1H), 8.47-8.40 (m, 1H), 7.46 (dd, J=8.8, 1.8 Hz, 1H), 7.40 (d, J=8.8Hz, 1H), 7.34 (dd, J=8.5, 6.7 Hz, 1H), 6.78 (td, J=8.2, 2.4 Hz, 1H),6.70 (dd, J=10.8, 2.4 Hz, 1H), 4.20 (s, 3H), 4.14 (t, J=6.3 Hz, 2H),3.18 (t, J=6.3 Hz, 2H), 2.74 (s, 3H), 2.24 (s, 3H).

Intermediate 8

2-(3-(benzamidomethyl)-[1,2,4]triazolo[4,3-a]pyridin-6-yl)-5-fluorophenylmethanesulfonate Step 1

A mixture of 5-bromo-2-hydrazinylpyridine (564 mg, 3.0 mmol) andhippuric acid (557 mg, 3.0 mmol) was heated to form a melt, which wasmaintained at 180° C. for one hour. The mixture solidified on coolingand the resulting solid was dissolved in warm methanol (10 ml). Theproduct,N-((6-bromo-[1,2,4]triazolo[4,3-a]pyridin-3-yl)methyl)benzamide,crystallised on cooling and was collected by filtration (320 mg, 32%).mp 208-209° C. ¹H NMR (400 MHz, DMSO-d6) δ 9.29 (t, J=5.6 Hz, 1H),9.02-8.94 (m, 1H), 7.93-7.84 (m, 2H), 7.78 (d, J=9.6 Hz, 1H), 7.58-7.44(m, 4H), 5.01 (d, J=5.5 Hz, 2H).

Step 2

A solution ofN-((6-bromo-[1,2,4]triazolo[4,3-a]pyridin-3-yl)methyl)benzamide (260 mg,0.78 mmol) was dissolved in dioxane (5 ml) and treated with4-fluoro-2-hydroxybenzene boronic acid (250 mg, 1.6 mmol) andtetrakis(triphenylphosphine) palladium(0) (10 mg), followed by asolution of potassium phosphate (432 mg, 2.0 mmol) in water (1 ml). Thereaction mixture was heated under reflux for 2 hr, cooled to roomtemperature and evaporated under reduced pressure. The residue waspartitioned between ethyl acetate/methanol (10:1, 20 ml) and saturatedsodium bicarbonate solution (20 ml). The organic phase was dried overNa₂SO₄, concentrated under reduced pressure and the crude productpurified by flash column chromatography by elution with ethylacetate/methanol (100:0, then 90:10) to giveN-((6-(4-fluoro-2-hydroxyphenyl)-[1,2,4]triazolo[4,3-a]pyridin-3-yl)methyl)benzamideas a colourless solid (277 mg, 98%). mp 185-186° C. ¹H NMR (400 MHz,Methanol-d4) δ 8.74 (d, J=1.4 Hz, 1H); 7.89-7.82 (m, 2H), 7.79-7.68 (m,2H), 7.57-7.50 (m, 1H), 7.49-7.42 (m, 2H), 7.41-7.32 (m, 1H), 6.73-6.71(m, 1H), 6.69 (dq, J=4.5, 2.3 Hz, 1H), 5.17 (s, 2H).

Step 3

A solution ofN-((6-(4-fluoro-2-hydroxyphenyl)-[1,2,4]triazolo[4,3-a]pyridin-3-yl)methyl)benzamide(157 mg, 0.43 mmol) in dichloromethane (10 ml) was cooled to 0° C. thentreated with triethylamine (120 μl, 0.86 mmol) followed bymethanesulfonyl chloride (67 μl, 0.86 mmol). The reaction mixture wasallowed to warm to room temperature and was stirred for 18 hours beforebeing quenched with saturated sodium bicarbonate solution (10 ml).Dichloromethane (20 ml) was added and the layers were separated. Theaqueous phase was further extracted with dichloromethane (20 ml) and thecombined organic extracts were dried (Na₂SO₄) and concentrated underreduced pressure. The crude product was purified by columnchromatography by elution with ethyl acetate/methanol/diethylamine(90:5:5). Fractions containing the product were combined and evaporatedto give2-(3-(benzamidomethyl)-[1,2,4]triazolo[4,3-a]pyridin-6-yl)-5-fluorophenylmethanesulfonate as a colourless solid (135 mg, 71%). mp 208-210° C. ¹HNMR (400 MHz, Methanol-d4) δ 8.82 (s, 1H), 7.89-7.81 (m, 3H), 7.70-7.61(m, 2H), 7.59-7.52 (m, 1H), 7.47 (t, J=7.6 Hz, 2H), 7.41 (dd, J=9.1, 2.5Hz, 1H), 7.31 (td, J=8.3, 2.7 Hz, 1H), 5.17 (s, 2H), 3.07 (s, 3H).

Intermediate 9

5-(5-fluoro-2-(2-(1,3,5-trimethyl-1H-pyrazol-4-yl)ethoxy)phenyl)-1-methyl-1H-indazole-3-carbaldehydeStep 1

A solution of 5-iodo-1-methyl-1H-indazole-3-carbaldehyde (prepared as inintermediate 4, step 2) (600 mg, 1.75 mmol) was dissolved in dioxane (15mL) and treated with 5-fluoro-2-hydroxybenzene boronic acid (355 mg, 1.3mmol) and tetrakis(triphenylphosphine) palladium(0) (50 mg), followed bya solution of potassium phosphate (744 mg, 2.0 mmol) in water (4.5 mL).The reaction mixture was heated under reflux for 2 hr, cooled to roomtemperature and evaporated under reduced pressure. The residue waspartitioned between ethyl acetate (20 mL) and saturated sodiumbicarbonate solution (20 mL). The organic phase was dried over Na₂SO₄,concentrated under reduced pressure and the crude product purified byflash column chromatography by elution with EtOAc/hexane (0-20% EtOAc)to give 5-(5-fluoro-2-hydroxyphenyl)-1methyl-1H-indazole-3-carbaldehydeas a yellow solid (213 mg, 45%). ¹H NMR (400 MHz, CDCl₃) δ 10.23 (s,1H), 8.43 (d, J=1.2 Hz, 1H), 7.70-7.54 (m, 1H), 7.14-6.89 (m, 4H), 5.10(s, 1H), 4.26 (s, 3H).

Step 2

A solution of5-(5-fluoro-2-hydroxyphenyl)-1-methyl-1H-indazole-3-carbaldehyde (200mg; 0.74 mmol) and triphenylphosphine (388 mg; 1.48 mmol) in THF (4 mL)was treated with a solution of2-(1,3,5-trimethyl-1H-pyrazol-4-yl)ethanol (228 mg, 1.48 mmol) in THF (3mL). The reaction mixture was cooled to 0° C. before being treated withdi-isopropyl azodicarboxylate (291 μl, 1.48 mmol). The reaction mixturewas allowed to warm to room temperature, stirred overnight andconcentrated under reduced pressure. The crude product was purified byautomated column chromatography by elution with hexane/IPA (gradient of95:5 to 40:60) to give the title compound as a colourless oil (155 mg,52%); ¹H NMR (400 MHz, CDCl₃) δ 10.26 (s, 1H), 8.51-8.37 (m, 1H), 7.64(dd, J=8.8, 1.7 Hz, 1H), 7.50 (d, J=8.8 Hz, 1H), 7.12 (dd, J=9.0, 3.1Hz, 1H), 7.01 (td, J=8.3, 3.1 Hz, 1H), 6.90 (dd, J=9.0, 4.6 Hz, 1H),4.25 (s, 3H), 3.92 (t, J=7.2 Hz, 2H), 3.65 (s, 3H), 2.73 (t, J=7.2 Hz,2H), 2.06 (s, 3H), 1.98 (s, 3H).

Intermediate 10

5-(3-fluoro-2-(2-(1,3,5-trimethyl-1H-pyrazol-4-yl)ethoxy)phenyl)-1-methyl-1H-indazole-3-carbaldehydeStep 1

A solution of 5-iodo-1-methyl-1H-indazole-3-carbaldehyde (prepared as inintermediate 4, step 2) (600 mg, 1.75 mmol) was dissolved in dioxane (15mL) and treated with 3-fluoro-2-hydroxybenzene boronic acid (355 mg, 1.3mmol) and tetrakis(triphenylphosphine) palladium(0) (50 mg), followed bya solution of potassium phosphate (744 mg, 2.0 mmol) in water (4.5 mL).The reaction mixture was heated under reflux for 2 hr, cooled to roomtemperature and evaporated under reduced pressure. The residue waspartitioned between ethyl acetate (20 mL) and saturated sodiumbicarbonate solution (20 mL). The organic phase was dried over Na₂SO₄,concentrated under reduced pressure and the crude product trituratedfrom EtOAc/hexane to give5-(3-fluoro-2-hydroxyphenyl)-1methyl-1H-indazole-3-carbaldehyde as anorange solid (388 mg, 82%). ¹H NMR (400 MHz, CDCl₃) δ 10.26 (s, 1H),8.49 (d, J=2.0 Hz, 1H), 7.77 (dd, J=8.8, 1.5 Hz, 1H), 7.57 (d, J=8.8 Hz,1H), 7.23-7.19 (m, 1H), 7.18-7.11 (m, 1H), 7.01-6.94 (m, 1H), 5.39 (d,J=5.4 Hz, 1H), 4.25 (s, 3H).

Step 2

A solution of5-(3-fluoro-2-hydroxyphenyl)-1-methyl-1H-indazole-3-carbaldehyde (350mg; 1.30 mmol) and triphenylphosphine (679 mg; 2.59 mmol) in THF (7 mL)was treated with a solution of2-(1,3,5-trimethyl-1H-pyrazol-4-yl)ethanol (399 mg, 2.59 mmol) in THF (5mL). The reaction mixture was cooled to 0° C. before being treated withdi-isopropyl azodicarboxylate (510 μl, 2.59 mmol). The reaction mixturewas allowed to warm to room temperature, stirred overnight andconcentrated under reduced pressure. The crude product was purified byautomated column chromatography by elution with hexane/IPA (gradient of95:5 to 40:60) to give the title compound as a colourless oil (490 mg,93%); ¹H NMR (400 MHz, CDCl₃) δ 10.27 (s, 1H), 8.40 (s, 1H), 7.68-7.60(m, 1H), 7.47 (d, J=8.8 Hz, 1H), 7.23-7.09 (m, 3H), 4.27 (s, 3H), 3.78(t, J=7.4 Hz, 2H), 3.60 (s, 3H), 2.60 (t, J=7.4 Hz, 3H), 1.96 (s, 6H).

Intermediate 11

2-(3-((dimethylamino)methyl)-[1,2,4]triazolo[4,3-a]pyridin-6-yl)-5-fluorophenylmethanesulfonate Step 1

A solution of 5-bromo-2-hydrazinylpyridine (564 mg, 3.0 mmol) in DCM (10ml) was treated with hydroxybenztriazole (40 mg, 0.3 mmol) followed byN,N-dimethylglycine (340 mg, 3.5 mmol) and finally EDCI (632 mg, 3.5mmol) by portionwise addition. The solution was stirred at roomtemperature overnight, then washed with water, dried (Na₂SO₄) andconcentrated under reduced pressure. The crude intermediate wasdissolved in THF (50 ml) and treated with triphenylphosphine (1.57 g, 6mmol) and triethylamine (1.67 ml, 12 mmol), followed by portionwiseaddition of hexachloroethane (1.42 g, 6 mmol). The mixture was stirredat room temperature overnight, then filtered. The filtrate wasconcentrated under reduced pressure and purified by SCX chromatographyby elution with methanolic ammonia (2M). Fractions containing theproduct were combined and evaporated to give1-(6-bromo-[1,2,4]triazolo[4,3-a]pyridin-3-yl)-N,N-dimethylmethanamineas an orange solid (387 mg, 51%) mp 167-169° C. ¹H NMR (400 MHz,Methanol-d4) δ 8.79 (t, J=1.5 Hz, 1H), 7.71 (d, J=9.8 Hz, 1H), 7.58 (dd,J=9.8, 1.5 Hz, 1H), 4.05 (s, 2H), 2.32 (s, 6H).

Step 2

A solution of1-(6-bromo-[1,2,4]triazolo[4,3-a]pyridin-3-yl)-N,N-dimethylmethanamine(387 mg, 1.5 mmol) was dissolved in dioxane (5 ml) and treated with4-fluoro-2-hydroxybenzene boronic acid (467 mg, 3.0 mmol) andtetrakis(triphenylphosphine) palladium(0) (20 mg), followed by asolution of potassium phosphate (810 mg, 3.75 mmol) in water (1 ml). Thereaction mixture was heated under reflux overnight, cooled to roomtemperature and evaporated under reduced pressure. The residue waspartitioned between ethyl acetate (20 ml) and water (20 ml). The organicphase was dried over Na₂SO₄, concentrated under reduced pressure and thecrude product purified by flash column chromatography by elution withethyl acetate/methanol/diethylamine (95:0:5, then 90:5:5) to give2-(3-((dimethylamino)methyl)-[1,2,4]triazolo[4,3-a]pyridin-6-yl)-5-fluorophenolas a yellow solid (193 mg, 45%). ¹H NMR (400 MHz, Methanol-d4) δ 8.62(d, J=1.4 Hz, 1H), 7.75-7.61 (m, 2H), 7.35 (dd, J=8.5, 6.7 Hz, 1H), 6.70(dd, J=10.7, 2.5 Hz, 1H), 6.62 (td, J=8.3, 2.5 Hz, 1H), 4.03 (s, 2H),2.30 (s, 6H).

Step 3

A solution of2-(3-((dimethylamino)methyl)-[1,2,4]triazolo[4,3-a]pyridin-6-yl)-5-fluorophenol(193 mg, 0.67 mmol) in dichloromethane (5 ml) was cooled to 0° C. thentreated with triethylamine (500 μl. 4.0 mmol) followed bymethanesulfonyl chloride (300 μl, 4.0 mmol). The reaction mixture wasallowed to warm to room temperature and was stirred for 18 hours beforebeing quenched with saturated sodium carbonate solution (2M, 20 ml).Dichloromethane (20 ml) was added and the layers were separated. Theaqueous phase was further extracted with dichloromethane (20 ml) and thecombined organic extracts were dried (Na₂SO₄) and concentrated underreduced pressure. The crude product was purified by columnchromatography by elution with ethyl acetate then ethylacetate/diethylamine (95:5). Fractions containing the product werecombined and evaporated to give2-(3-((dimethylamino)methyl)-[1,2,4]triazolo[4,3-a]pyridin-6-yl)-5-fluorophenylmethanesulfonate as a orange solid (110 mg, 45%) mp 161-163° C. ¹H NMR(400 MHz, Chloroform-d) δ 8.52 (d, J=1.6 Hz, 1H), 7.81-7.73 (m, 1H),7.48 (dd, J=8.7, 6.1 Hz, 1H), 7.37 (dd, J=9.6, 1.7 Hz, 1H), 7.30 (dd,J=8.8, 2.6 Hz, 1H), 7.22-7.12 (m, 1H), 4.00 (s, 2H), 3.02 (s, 3H), 2.26(s, 6H).

Intermediate 12

2-(3-(((tert-butoxycarbonyl)(methyl)amino)methyl)-[1,2,4]triazolo[4,3-a]pyridin-6-yl)-5-fluorophenylmethanesulfonate Step 1

A solution of 5-bromo-2-hydrazinylpyridine (1.12 g, 6.0 mmol) in DCM (20ml) was treated with hydroxybenztriazole (94 mg, 0.7 mmol) followed byN-Boc-sarcosine (1.25 g, 6.6 mmol) and finally EDCI (1.34 g, 7 mmol) byportionwise addition. The solution was stirred at room temperatureovernight, then washed with water, dried (Na₂SO₄) and concentrated underreduced pressure. The crude intermediate was dissolved in THF (70 ml)and treated with triphenylphosphine (3.14 g, 12 mmol) and triethylamine(3.34 ml, 24 mmol), followed by portionwise addition of hexachloroethane(2.84 g, 12 mmol). The mixture was stirred at room temperatureovernight, then filtered. The filtrate was concentrated under reducedpressure and purified by SCX chromatography by elution with methanolicammonia (2M). Fractions containing the product were combined andevaporated to give crude product, which was further purified by columnchromatography by elution with dichloromethane/ethyl acetate (1:1 then0:1). Fractions containing the major product were combined andevaporated under reduced pressure to give tert-butyl((6-bromo-[1,2,4]triazolo[4,3-a]pyridin-3-yl)methyl)(methyl)carbamate asa yellow solid (650 mg, 31%) mp 102-104° C. ¹H NMR (400 MHz,Chloroform-d) δ 8.76 (s, 1H), 7.63 (d, J=9.7 Hz, 1H), 7.30 (d, J=9.5 Hz,1H), 4.95 (s, 2H), 2.80 (s, 3H), 1.47 (s, 9H).

Step 2

A solution of tert-butyl((6-bromo-[1,2,4]triazolo[4,3-a]pyridin-3-yl)methyl)(methyl)carbamate(650 mg, 1.9 mmol) was dissolved in dioxane (8 ml) and treated with4-fluoro-2-hydroxybenzene boronic acid (592 mg, 3.8 mmol) andtetrakis(triphenylphosphine) palladium(0) (40 mg), followed by asolution of potassium phosphate (1.08 g, 4.75 mmol) in water (2 ml). Thereaction mixture was heated under reflux overnight, cooled to roomtemperature and evaporated under reduced pressure. The residue waspartitioned between ethyl acetate (20 ml) and water (20 ml). The organicphase was dried over Na₂SO₄, concentrated under reduced pressure and thecrude product purified by flash column chromatography by gradientelution with ethyl acetate/hexane (1:1), then ethyl acetate and thenethylacetate/methanol (95:5, then 90:10) to give tert-butyl((6-(4-fluoro-2-hydroxyphenyl)-[1,2,4]triazolo[4,3-a]pyridin-3-yl)methyl)(methyl)carbamateas a colourless solid (650 mg, ˜100%) mp 127-129° C. ¹H NMR (400 MHz,Methanol-d4) δ 8.67 (s, 1H), 7.84-7.67 (m, 2H), 7.37 (dd, J=8.9, 5.7 Hz,1H), 6.78-6.64 (m, 2H), 5.05 (s, 2H), 2.90 (s, 3H), 1.45 (s, 9H).

Step 3

A solution of tert-butyl((6-(4-fluoro-2-hydroxyphenyl)-[1,2,4]triazolo[4,3-a]pyridin-3-yl)methyl)(methyl)carbamate(650 mg, 1.9 mmol) in dichloromethane (5 ml) was cooled to 0° C. thentreated with triethylamine (560μ, 4.0 mmol) followed by methanesulfonylchloride (310 μl, 4.0 mmol). The reaction mixture was allowed to warm toroom temperature and was stirred for 18 hours before being quenched withsodium carbonate solution (2M, 20 ml). Dichloromethane (20 ml) was addedand the layers were separated. The aqueous phase was further extractedwith dichloromethane (20 ml) and the combined organic extracts weredried (Na₂SO₄) and concentrated under reduced pressure. The crudeproduct was purified by column chromatography by elution with ethylacetate then ethyl acetate/diethylamine (100:0 then 95:5). Fractionscontaining the product were combined and evaporated to give a foam whichwas triturated with cyclohexane to give2-(3-(((tert-butoxycarbonyl)(methyl)amino)-methyl)-[1,2,4]triazolo[4,3-a]pyridin-6-yl)-5-fluorophenylmethanesulfonate as a colourless solid (530 mg, 62%) mp 147-149° C. ¹HNMR (400 MHz, Chloroform-d) δ 8.69 (s, 1H), 7.84 (d, J=9.4 Hz, 1H), 7.49(d, J=9.9 Hz, 1H), 7.45 (dd, J=8.7, 6.2 Hz, 1H), 7.31 (dd, J=8.8, 2.5Hz, 1H), 7.22-7.09 (m, 1H), 5.03 (s, 2H), 3.00 (s, 3H), 2.89 (s, 3H),1.45 (s, 9H).

Intermediate 13

5-chloro-2-(3-((dimethylamino)methyl)-[1,2,4]triazolo[4,3-a]pyridin-6-yl)phenylmethanesulfonate Step 1

A solution of1-(6-bromo-[1,2,4]triazolo[4,3-a]pyridin-3-yl)-N,N-dimethylmethanamine[product of Step 1, Intermediate 11] (387 mg, 1.5 mmol) was dissolved indioxane (8 ml) and treated with 4-chloro-2-hydroxybenzene boronic acid(516 mg, 3.0 mmol) and tetrakis(triphenylphosphine) palladium(0) (20mg), followed by a solution of potassium phosphate (810 mg, 3.75 mmol)in water (1 ml). The reaction mixture was heated under reflux overnight,cooled to room temperature and evaporated under reduced pressure. Theresidue was partitioned between ethyl acetate (20 ml) and water (20 ml).The organic phase was dried over Na₂SO₄, concentrated under reducedpressure and the crude product purified by flash column chromatographyby elution with ethyl acetate/methanol/diethylamine (95:0:5, then90:5:5) to give5-chloro-2-(3-((dimethylamino)methyl)-[1,2,4]triazolo[4,3-a]pyridin-6-yl)phenolas a yellow solid (240 mg, 52%). ¹H NMR (400 MHz, Methanol-d4) δ 8.68(d, J=1.4 Hz, 1H), 7.79-7.64 (m, 2H), 7.35 (d, J=8.3 Hz, 1H), 6.96 (d,J=2.1 Hz, 1H), 6.89 (dd, J=8.1, 2.2 Hz, 1H), 4.06 (s, 2H), 2.31 (s, 6H).

Step 2

A solution of5-chloro-2-(3-((dimethylamino)methyl)-[1,2,4]triazolo[4,3-a]pyridin-6-yl)phenol(240 mg, 0.8 mmol) in dichloromethane (5 ml) was cooled to 0° C. thentreated with triethylamine (500 μl. 4.0 mmol) followed bymethanesulfonyl chloride (300 μl, 4.0 mmol). The reaction mixture wasallowed to warm to room temperature and was stirred for 18 hours beforebeing quenched with saturated sodium carbonate solution (2M, 20 ml).Dichloromethane (20 ml) was added and the layers were separated. Theaqueous phase was further extracted with dichloromethane (20 ml) and thecombined organic extracts were dried (Na₂SO₄) and concentrated underreduced pressure. The crude product was triturated with cyclohexane togive5-chloro-2-(3-((dimethylamino)methyl)-[1,2,4]triazolo[4,3-a]pyridin-6-yl)phenylmethanesulfonate as a orange solid (280 mg, 92%) mp 169-170° C. ¹H NMR(400 MHz, Chloroform-d) δ 8.55 (t, J=1.4 Hz, 1H), 7.84-7.75 (m, 1H),7.57 (d, J=1.8 Hz, 1H), 7.49-7.40 (m, 2H), 7.39 (dd, J=9.5, 1.6 Hz, 1H),4.02 (s, 2H), 3.04 (s, 3H), 2.28 (s, 6H).

Intermediate 14

tert-butyl2-{6-[4-fluoro-2-(methanesulfonyloxy)phenyl]-[1,2,4]triazolo[4,3-a]pyridin-3-yl}pyrrolidine-1-carboxylateStep 1

A solution of 5-bromo-2-hydrazinylpyridine (500 mg, 2.66 mmol) in DCM(10 ml) was treated with hydroxybenztriazole (48 mg, 0.31 mmol) followedby N-Boc-proline (642 mg, 3.0 mmol) and finally EDCI (621 mg, 3.2 mmol)by portionwise addition. The solution was stirred at room temperatureovernight, then washed with water and brine, dried (Na₂SO₄) andconcentrated under reduced pressure. The crude product was purified bycolumn chromatography by elution with dichloromethane/methanol (98:2).Fractions containing the product were combined and evaporated to givetert-butyl2-[N′-(5-bromo-1,2-dihydropyridin-2-ylidene)hydrazinecarbonyl]pyrrolidine-1-carboxylateas a brown solid (900 mg, 88%). ¹H NMR (400 MHz, DMSO-d6) δ 9.87 (d,J=10.2 Hz, 1H), 8.58 (d, J=6.7 Hz, 1H), 8.10 (s, 1H), 7.65 (m, 1H), 6.58(dd. 1H) 4.15 (m, 1H), 3.37 (d, 1H), 3.30 (m, 1H), 2.17 (m, 1H),1.80-1.86 (m, 4H), 1.40 (s, 9H), 1.23-1.38 (m, 4H).

Step 2

Tert-butyl2-[N′-(5-bromo-1,2-dihydropyridin-2-ylidene)hydrazinecarbonyl]pyrrolidine-1-carboxylate(900 mg, 2.33 mmol was dissolved in THF (20 ml) and treated withtriphenylphosphine (1.25 g, 4.67 mmol) and triethylamine (1.30 ml, 9.34mmol), followed by portionwise addition of hexachloroethane (1.10 g,4.67 mmol). The mixture was stirred at room temperature overnight, thenfiltered through Celite. The filtrate was concentrated under reducedpressure and purified by column chromatography on silica by elution withdichloromethane/methanol (98:2). Fractions containing the product werecombined and evaporated to give crude product, tert-butyl2-{6-bromo-[1,2,4]triazolo[4,3a]pyridin-3-yl}pyrrolidine-1-carboxylate(650 mg, 95.7%) as a mixture of rotamers. ¹H NMR (400 MHz, DMSO-d6) δ8.98 (d, 1H), 7.77 (dd, 1H), 7.64-7.54 (m, 1H), 7.47 (d, 1H), 3.42-3.33(m, 2H), 2.32-2.10 (m, 3H), 1.95-1.90 (m, 1H), 1.34-0.80 (m, 11H).

Step 3

A solution of tert-butyl2-{6-bromo-[1,2,4]triazolo[4,3a]pyridin-3-yl}pyrrolidine-1-carboxylate(300 mg, 0.8 mmol) was dissolved in dioxane (10 ml) and treated with4-fluoro-2-hydroxybenzene boronic acid (206 mg, 1.6 mmol) andtetrakis(triphenylphosphine) palladium(0) (94 mg), followed by asolution of potassium phosphate (433 mg, 2.0 mmol) in water (2 ml). Thereaction mixture was heated under reflux overnight, cooled to roomtemperature and filtered through Celite, washing with ethyl acetate andseparated. The organic phase was dried over Na₂SO₄, concentrated underreduced pressure and the crude product purified by flash columnchromatography by elution with dichloromethane/methanol (95:5) to givetert-butyl2-[6-(4-fluoro-2-hydroxyphenyl)-[1,2,4]triazolo[4,3-a]pyridin-3-yl]pyrrolidine-1-carboxylate(280 mg, 86%). ¹H NMR (400 MHz, DMSO-d6) δ 10.45 (s, 1H), 8.61 (d, 1H),7.75 (m, 1H), 7.62-7.56 (m, 2H), 7.39 (m, 1H), 6.77 (m, 2H), 5.47 (m,1H), 3.50 (m, 2H), 2.32-1.96 (m, 4H), 1.33-0.91 (m, 11H).

Step 4

A solution of tert-butyl2-[6-(4-fluoro-2-hydroxyphenyl)-[1,2,4]triazolo[4,3-a]pyridin-3-yl]pyrrolidine-1-carboxylate(80 mg, 0.2 mmol) in dichloromethane (5 ml) was cooled to 0° C. thentreated with triethylamine (59 μL, 0.4 mmol) followed by methanesulfonylchloride (33 μl, 0.42 mmol). The reaction mixture was allowed to warm toroom temperature and was stirred for 18 hours before being quenched withsodium bicarbonate solution (2M, 20 ml). Dichloromethane (20 ml) wasadded and the layers were separated. The aqueous phase was furtherextracted with dichloromethane (20 ml) and the combined organic extractswere dried (Na₂SO₄) and concentrated under reduced pressure. The crudeproduct was purified by column chromatography by gradient elution withdichloromethane/methanol (99:1-95:5). Fractions containing the productwere combined and evaporated to give the product, tert-butyl2-{6-[4-fluoro-2-(methanesulfonyloxy)phenyl]-[1,2,4]triazolo[4,3-a]pyridin-3-yl}pyrrolidine-1-carboxylateas a solid (75 mg, 78%). ¹H NMR (400 MHz, Chloroform-d) δ 8.73 (s, 1H),7.78 (m, 1H), 7.68-7.62 (m, 1H), 7.45 (m, 1H), 7.37 (d, 1H) 7.30 (d,1H), 7.16 (m, 1H), 5.35 (m, 1H), 3.69-3.54 (m, 2H), 2.72 (s, 3H),2.61-2.58 (m, 2H), 2.30 (m, 1H), 2.05 (m, 1H), 1.56-1.02 (m, 11H).

Intermediate 15

Tert-butyl3-{6-[4-fluoro-2-(methanesulfonyloxy)phenyl]-[1,2,4]triazolo[4,3-a]pyridin-3-yl}azetidine-1-carboxylateStep 1

A solution of 5-bromo-2-hydrazinylpyridine (1.0 g, 5.32 mmol) in DCM (10ml) was treated with hydroxybenztriazole (98 mg, 0.64 mmol) followed byN-Boc-azetidine-3-carboxylic acid (1.17 g, 5.85 mmol) and finally EDCI(1.22 g, 6.38 mmol) by portionwise addition. The solution was stirred atroom temperature overnight, then washed with saturated sodiumbicarbonate, water and brine, dried (Na₂SO₄) and concentrated underreduced pressure. The crude product was purified by columnchromatography by elution with dichloromethane/methanol (96:4).Fractions containing the product were combined and evaporated to givetert-butyl3-[N′-(5-bromopyridin-2-yl)hydrazinecarbonyl]azetidine-1-carboxylate asa solid (1.95 g, 99%). ¹H NMR (400 MHz, DMSO-d6) δ 9.90 (s, 1H), 8.61(s, 1H), 8.12 (s, 1H), 7.68 (d, 1H), 6.55 (d, 1H), 5.75 (s, 1H), 3.98(s, 2H), 3.85 (s, 2H), 1.36 (s, 9H).

Step 2

Tert-butyl3-[N′-(5-bromopyridin-2-yl)hydrazinecarbonyl]azetidine-1-carboxylate(1.95 g, 5.25 mmol was dissolved in THF (50 ml) and treated withtriphenylphosphine (2.75 g, 10.5 mmol) and triethylamine (2.93 ml, 21mmol), followed by portionwise addition of hexachloroethane (2.48 g,10.5 mmol). The mixture was stirred at room temperature overnight, thenfiltered through Celite. The filtrate was washed with ethyl acetate,dried (Na₂SO₄), concentrated under reduced pressure and purified bycolumn chromatography on silica by elution with dichloromethane/methanol(98:2). Fractions containing the product were combined and evaporated togive crude product, tert-butyl3-{6-bromo-[1,2,4]triazolo[4,3-a]pyridin-3-yl}azetidine-1-carboxylate(1.40 g, 75%) as a brown solid. ¹H NMR (400 MHz, Chloroform-d) δ 8.01(s, 1H), 7.68 (d, 1H), 7.31 (d, 1H), 4.44 (m, 4H), 4.15 (m, 1H), 1.45(s, 9H).

Step 3

A solution of tert-butyl3-{6-bromo-[1,2,4]triazolo[4,3-a]pyridin-3-yl}azetidine-1-carboxylate(500 mg, 1.4 mmol) was dissolved in dioxane (10 ml) and treated with4-fluoro-2-hydroxybenzene boronic acid (357 mg, 2.8 mmol) andtetrakis(triphenylphosphine) palladium(0) (163 mg), followed by asolution of potassium phosphate (751 mg, 3.5 mmol) in water (2 ml). Thereaction mixture was heated under reflux overnight, cooled to roomtemperature and filtered through Celite, washing with ethyl acetate andseparated. The organic phase was dried over Na₂SO₄, concentrated underreduced pressure and the crude product purified by flash columnchromatography by gradient elution with dichloromethane/methanol(97:3-95:5) to give tert-butyl3-[6-(4-fluoro-2-hydroxyphenyl)-[1,2,4]triazolo[4,3-a]pyridin-3-yl]azetidine-1-carboxylate(440 mg, 81%). ¹H NMR (400 MHz, Chloroform-d) δ 9.5 (br. s, 1H), 8.11(s, 1H), 7.71 (d, 1H), 7.52 (d, 1H), 7.25 (m, 1H), 6.84 (m, 1H), 6.69(m, 1H), 4.43 (m, 4H), 4.21 (m, 1H), 1.44 (s, 9H).

Step 4

A solution of tert-butyl3-[6-(4-fluoro-2-hydroxyphenyl)-[1,2,4]triazolo[4,3-a]pyridin-3-yl]azetidine-1-carboxylate(250 mg, 0.65 mmol) in dichloromethane (5 ml) was cooled to 0° C. thentreated with triethylamine (190 μL, 1.36 mmol) followed bymethanesulfonyl chloride (106 μl, 1.36 mmol). The reaction mixture wasallowed to warm to room temperature and was stirred for 18 hours beforebeing quenched with sodium bicarbonate solution (2M, 20 ml).Dichloromethane (20 ml) was added and the layers were separated. Theorganic phase was washed with water and brine then dried (Na₂SO₄) andconcentrated under reduced pressure. The crude product was purified bycolumn chromatography by gradient elution with dichloromethane/methanol(99:1-98:2). Fractions containing the product were combined andevaporated to give the product, tert-butyl3-{6-[4-fluoro-2-(methanesulfonyloxy)phenyl]-[1,2,4]triazolo[4,3-a]pyridin-3-yl}azetidine-1-carboxylateas a solid (260 mg, 86%). ¹H NMR (400 MHz, DMSO-d6) δ 8.45 (s, 1H), 7.85(d, 1H), 7.72 (m, 1H), 7.53 (dd, 1H), 7.48 (d, 1H) 7.45 (m, 1H),4.38-4.24 (m, 5H), 3.30 (s, 3H), 2.61-2.58 (m, 2H), 2.30 (m, 1H), 2.05(m, 1H), 1.39 (s, 9H).

Intermediate 16

tert-butylN-(2-{6-[4-fluoro-2-(methanesulfonyloxy)phenyl]-[1,2,4]triazolo[4,3-a]pyridin-3-yl}ethyl)-N-methylcarbamateStep 1

A solution of 5-bromo-2-hydrazinylpyridine (500 mg, 2.66 mmol) in DCM(10 ml) was treated with hydroxybenztriazole (49 mg, 0.32 mmol) followedby N-Boc-β-alanine (605 mg, 2.98 mmol) and finally EDCI (611 mg, 3.19mmol) by portionwise addition. The solution was stirred at roomtemperature overnight, then washed with water and brine, dried (Na₂SO₄)and concentrated under reduced pressure. The crude product was purifiedby column chromatography by gradient elution withdichloromethane/methanol (99:1-97:3). Fractions containing the productwere combined and evaporated to give tert-butylN-{2-[N′-(5-bromo-1,2-dihydropyridin-2-ylidene)hydrazinecarbonyl]ethyl}-N-methylcarbamateas a gum (850 mg; 86%). ¹H NMR (400 MHz, DMSO-d6) δ 9.84 (s, 1H), 8.54(s, 1H), 8.11 (s, 1H), 7.66 (d, 1H), 6.52 (d, 1H), 3.37 (t, 2H), 2.77(s, 3H), 2.39 (t, 2H), 1.40 (s, 9H).

Step 2

Tert-butylN-{2-[N′-(5-bromo-1,2-dihydropyridin-2-ylidene)hydrazinecarbonyl]ethyl}-N-methylcarbamate(850 mg, 2.28 mmol was dissolved in THF (20 ml) and treated withtriphenylphosphine (1.19 g, 4.56 mmol) and triethylamine (1.27 ml, 9.1mmol), followed by portionwise addition of hexachloroethane (1.08 g,4.56 mmol). The mixture was stirred at room temperature overnight, thenfiltered through Celite. The filtrate was washed with ethyl acetate,dried (Na₂SO₄), concentrated under reduced pressure and purified bycolumn chromatography on silica by elution with dichloromethane/methanol(97:3). Fractions containing the product were combined and evaporated togive crude product, tert-butylN-(2-{6-bromo-[1,2,4]triazolo[4,3-a]pyridin-3-yl}ethyl)-N-methylcarbamate(600 mg, 74%) as a solid. ¹H NMR (400 MHz, DMSO-d6) indicated a mixtureof rotamers 6 8.84 (d, 1H), 7.73 (dd, 1H), 7.45 (dd, 1H), 3.58 (t, 2H),3.16 (t, 2H), 2.80 (s, 3H) 1.16 (d, 9H).

Step 3

A solution of tert-butylN-(2-{6-bromo-[1,2,4]triazolo[4,3-a]pyridin-3-yl}ethyl)-N-methylcarbamate(300 mg, 0.84 mmol) was dissolved in dioxane (10 ml) and treated with4-fluoro-2-hydroxybenzene boronic acid (213 mg, 1.7 mmol) andtetrakis(triphenylphosphine) palladium(0) (98 mg), followed by asolution of potassium phosphate (448 mg, 2.1 mmol) in water (2 ml). Thereaction mixture was heated under reflux overnight under an argonatmosphere, cooled to room temperature and filtered through Celite,washing with ethyl acetate and separated. The organic phase was driedover Na₂SO₄, concentrated under reduced pressure and the crude productpurified by flash column chromatography by elution withdichloromethane/methanol (95:5) to give tert-butylN-{2-[6-(4-fluoro-2-hydroxyphenyl)-[1,2,4]triazolo[4,3-a]pyridin-3-yl]ethyl}-N-methylcarbamateas a brown solid (250 mg, 77%). ¹H NMR (400 MHz, DMSO-d6) indicates amixture of rotamers 6 10.39 (s, 1H), 8.44 (s, 1H), 7.74-7.66 (m, 2H),7.53 (d, 1H), 7.41 (m, 1H), 6.77 (m, 2H), 3.60 (m, 2H), 3.32 (m, 2H),2.83 (s, 3H), 1.13 (d, 9H).

Step 4

A solution of tert-butylN-{2-[6-(4-fluoro-2-hydroxyphenyl)-[1,2,4]triazolo[4,3-a]pyridin-3-yl]ethyl}-N-methylcarbamate(250 mg, 0.65 mmol) in dichloromethane (5 ml) was cooled to 0° C. thentreated with triethylamine (189 μL, 1.36 mmol) followed bymethanesulfonyl chloride (105 μl, 1.36 mmol). The reaction mixture wasallowed to warm to room temperature and was stirred for 18 hours beforebeing quenched with sodium bicarbonate solution (2M, 20 ml).Dichloromethane (20 ml) was added and the layers were separated. Theorganic phase was washed with water and brine then dried (Na₂SO₄) andconcentrated under reduced pressure. The crude product was purified bycolumn chromatography by gradient elution with dichloromethane/methanol(99:1-98:2). Fractions containing the product were combined andevaporated to give the product, tert-butylN-(2-{6-[4-fluoro-2-(methanesulfonyloxy)phenyl]-[1,2,4]triazolo[4,3-a]pyridin-3-yl}ethyl)-N-methylcarbamateas a solid (220 mg, 73%). ¹H NMR (400 MHz, DMSO-d6) indicates a mixtureof rotamers 6 8.56 (d, 1H), 7.81 (dd, 1H), 7.69 (dd, 1H), 7.54 (dd, 1H),7.45 (m, 2H), 3.60 (m, 2H), 3.35 (m, 2H), 3.25 (s, 3H), 2.80 (d, 3H),1.13 (d, 9H).

Intermediate 17

5-(3,4-difluoro-2-(2-(1,3,5-trimethyl-1H-pyrazol-4-yl)ethoxy)phenyl)-1-methyl-1H-indazole-3-carbaldehydeStep 1

A solution of 5-iodo-1-methyl-1H-indazole-3-carbaldehyde (prepared as inintermediate 4, step 2) (1.0 g, 3.5 mmol) was dissolved in dioxane (10mL) and treated with 3,4-difluoro-2-hydroxybenzene boronic acid (880 mg,5 mmol) and tetrakis(triphenylphosphine) palladium(0) (30 mg), followedby a solution of potassium phosphate (1.06 g, 5.0 mmol) in water (2 mL).The reaction mixture was heated under reflux for 1 hr, cooled to roomtemperature and evaporated under reduced pressure. The residue waspartitioned between ethyl acetate/methanol (10:1, 100 mL) and brine (50mL). The aqueous phase was re-extracted with ethyl acetate/methanol(10:1, 50 mL), and the combined organic extract was dried over Na₂SO₄,concentrated under reduced pressure and the crude product trituratedfrom ethyl acetate to give5-(3,4-difluoro-2-hydroxyphenyl)-1-methyl-1H-indazole-3-carbaldehyde asan orange solid (483 mg, 48%) mp 216-218° C. ¹H NMR (400 MHz, DMSO-d6) δ10.36 (s, 1H), 10.16 (s, 1H), 8.25 (d, J=1.5 Hz, 1H), 7.88 (d, J=8.8 Hz,1H), 7.69 (dd, J=8.8, 1.6 Hz, 1H), 7.18 (ddd, J=8.6, 6.1, 2.1 Hz, 1H),7.05-6.91 (m, 1H), 4.25 (s, 3H).

Step 2

A solution of5-(3,4-difluoro-2-hydroxyphenyl)-1-methyl-1H-indazole-3-carbaldehyde(374 mg; 1.30 mmol) and triphenylphosphine (679 mg; 2.59 mmol) in THF (7mL) was treated with a solution of2-(1,3,5-trimethyl-1H-pyrazol-4-yl)ethanol (399 mg, 2.59 mmol) in THF (5mL). The reaction mixture was cooled to 0° C. before being treated withdi-isopropyl azodicarboxylate (510 μl, 2.59 mmol). The reaction mixturewas allowed to warm to room temperature, stirred overnight andconcentrated under reduced pressure. The crude product was purified bycolumn chromatography by gradient elution with hexane/IPA (80:20 to70:30) to give the title compound as a colourless solid (320 mg, 58%) mp173-174° C. ¹H NMR (400 MHz, Chloroform-d) δ 10.25 (s, 1H), 8.35 (d,J=1.6 Hz, 1H), 7.59 (dd, J=8.8, 1.5 Hz, 1H), 7.46 (d, J=8.6 Hz, 1H),7.12 (ddd, J=8.3, 5.9, 2.2 Hz, 1H), 6.99 (td, J=9.1, 7.2 Hz, 1H), 4.26(s, 3H), 3.80 (t, J=7.5 Hz, 2H), 3.60 (s, 3H), 2.60 (t, J=7.5 Hz, 2H),1.96 (s, 3H), 1.94 (s, 3H).

Intermediate 18

2-(3-((dimethylamino)methyl)-1-methyl-1H-indazol-5-yl)-6-fluorophenylmethanesulfonate Step 1

To a solution of 5-iodo-1-methyl-1H-indazole-3-carbaldehyde (prepared asin intermediate 4, step 2) (1.0 g, 3.5 mmol) (1.00 g, 3.50 mmol) in1,4-dioxane (10 mL) was added 3-fluoro-2-hydroxyphenyl boronic acid(1.00 g, 6.41 mmol), tetrakis(triphenylphosphine)palladium(0) (30 mg,0.026 mmol) and an aqueous solution (3 mL) of potassium phosphate (1.72g, 8.75 mmol). The yellowish orange solution was refluxed at 107° C. for2.5 hr to give a reddish brown mixture which was then concentrated underreduced pressure. EtOAc (40 mL) and saturated aqueous sodium carbonatesolution (2×20 mL) was added to extract the product and the organiclayer was dried over Na₂SO₄, concentrated in vacuo to give an orangepowder. The crude product was purified by flash column chromatography byelution with 5% EtOAc in DCM to give5-(3-fluoro-2-hydroxyphenyl)-1-methyl-1H-indazole-3-carbaldehyde as afluffy white solid (461 mg, 49%). m.p. 211-212° C.; ¹H NMR (DMSO-d₆, 400MHz, 300 K) 6 10.16 (1H, s), 9.72 (1H, d, J=1.6 Hz), 8.29 (1H, dd,J=1.7, 0.8 Hz), 7.87 (1H, dd, J=8.8, 0.9 Hz), 7.72 (1H, dd, J=8.8, 1.6Hz), 7.23-7.16 (2H, m), 6.93 (1H, td, J=8.0, 5.2 Hz), 4.25 (3H, s).

Step 2

To a pale yellow solution of5-(3-fluoro-2-hydroxyphenyl)-1-methyl-1H-indazole-3-carbaldehyde (461mg, 1.71 mmol) in anhydrous THF (10 mL) at 0° C. was added triethylamine(0.48 mL, 3.4 mmol), methanesulfonyl chloride (0.26 mL, 3.4 mmol). Theresulting cloudy white mixture was stirred for 18 hr to give a paleyellow mixture. Saturated. aqueous sodium bicarbonate solution (10 mL)was added to quench the reaction. EtOAc (2×30 mL) was added to extractthe product. The combined organic layers were dried over Na₂SO₄,concentrated in vacuo to give2-fluoro-6-(3-formyl-1-methyl-1H-indazol-5-yl)phenyl methanesulfonate asa pale yellow solid (584 mg, 98%). ¹H NMR (CDCl₃, 400 MHz, 300 K) 610.23 (1H, s), 8.43 (1H, s), 7.70 (1H, dd, J=8.7, 1.6 Hz), 7.57 (1H, dd,J=8.8, 0.9 Hz), 7.39-7.22 (3H, m,), 4.23 (3H, s), 2.88 (3H, s).

Step 3

To 2-fluoro-6-(3-formyl-1-methyl-1H-indazol-5-yl)phenyl methanesulfonate(584 mg, 1.68 mmol) in 1,2-dichloroethane (DCE) was added dimethylamine(2M in THF, 2.6 mL, 5.1 mmol) and glacial acetic acid (0.59 mL, 10 mmol)to give a yellow mixture which was stirred at room temperature for 10min. Sodium triacetoxyborohydride (95%, 1.14 g, 5.1 mmol) was then addedand the yellow mixture was stirred at room temperature for 16 hr. Sodiumcarbonate solution (2M, 40 mL) was added to quench the reaction. DCM(2×25 mL) was added to extract the product and the combined organiclayer was dried over Na₂SO₄, concentrated in vacuo to give a yellow oil.The crude product was purified by flash column chromatography by elutionwith 5% diethylamine in EtOAc to give2-(3-((dimethylamino)methyl)-1-methyl-1H-indazol-5-yl)-6-fluorophenylmethanesulfonate as a viscous yellow oil (542 mg, 86%). ¹H NMR (CDCl₃,400 MHz, 300 K) 6 7.98 (1H, dd, J=1.6, 0.8 Hz), 7.55 (1H, dd, J=8.7, 1.6Hz), 7.44 (1H, dd, J=8.7, 0.7 Hz), 7.37-7.19 (3H, m), 4.07 (3H, s), 3.82(2H, s), 2.73 (3H, s), 2.31 (6H, s).

Intermediate 19

2-(1,3,5-trimethyl-1H-pyrazol-4-yl)oct-7-yn-1-ol Step 1

To sodium hydride (60% in mineral oil, 1.69 g, 42.3 mmol) in anhydroustetrahydrofuran (THF) (120 mL) at 0° C. was added acetylacetone (4.1 mL,40 mmol) to give a cloudy white mixture which was stirred for 1 hr.Ethyl bromoacetate (5.3 mL, 48 mmol) was then added and the mixture wasstirred for 18 hr. The cloudy yellow reaction mixture was washed withsaturated aqueous ammonium chloride solution (100 mL). The aqueous layerwas back extracted with ethyl acetate (2×100 mL). The combined organiclayers were washed with brine (100 mL), dried over magnesium sulfate(MgSO₄) and concentrated in vacuo to give Ethyl 3-acetyl-4-oxopentanoateas a yellow oil (7.18 g, 96%). Diketone ¹H NMR (CDCl₃, 400 MHz, 300 K) 64.18-4.01 (3H, m), 2.80 (2H, d, J=7.3 Hz), 2.19 (6H, s), 1.24-1.15 (3H,m); Enol δ_(H)/ppm ¹H NMR (CDCl₃, 400 MHz, 300 K) 6 4.18-4.01 (2H, m),3.18 (2H,), 2.08 (6H, s), 1.24-1.15 (3H, m).

Step 2

Methylhydrazine (2.6 mL, 42 mmol) was added dropwise to Ethyl3-acetyl-4-oxopentanoate (7.18 g, 38.6 mmol) in acetic acid (60 mL) at0° C. and the yellow solution was stirred at room temperature for 20 hr.The majority of acetic acid was removed in vacuo and the residue wasneutralised by saturated aqueous sodium carbonate solution (100 mL).Ethyl acetate (100 mL) was added to extract the product and the yelloworganic layer was washed with brine (100 mL), dried over MgSO₄ andconcentrated in vacuo. The crude product was purified by flash columnchromatography by elution with 2% methanol in dichloromethane to givethe Ethyl 2-(1,3,5-trimethyl-1H-pyrazol-4-yl)acetate as a yellow oil(3.99 g, 53%). ¹H NMR (CDCl₃, 400 MHz, 300 K) 6 4.06 (3H, q, J=7.1 Hz),3.65 (3H, s), 3.27 (2H, s), 2.13 (6H, s,), 1.19 (3H, t).

Step 3

To a solution of diisopropylamine (0.86 mL, 6.1 mmol) in anhydrous THF(10 mL) at 0° C. was added n-butyllithium (2.5M in hexane) undernitrogen to give a light yellow solution which was stirred at roomtemperature for 10 min. Ethyl 2-(1,3,5-trimethyl-1H-pyrazol-4-yl)acetate(1.00 g, 5.10 mmol) was added at −78° C. and the yellowish orangemixture was stirred at −78° C. for 1 hr. 6-iodo-1-hexyne (0.78 mL, 5.9mmol) was added to give orange mixture which was stirred at −78° C. foranother 1 hr before the addition of 1,3-Dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (DMPU). The mixture was slowly warmed to 0° C. in 1 hrand water (5 mL) was added to quench the reaction. Ethyl acetate (3×200mL) was used to extract the product and the organic layer was washedwith saturated aqueous ammonium chloride solution (20 mL), hydrochloricacid (1M, 20 mL), saturated aqueous sodium carbonate solution (20 mL),brine (20 mL), dried over MgSO₄ and concentrated in vacuo to give anorange liquid. The crude product was purified by flash columnchromatography by elution with 50% ethyl acetate in hexane to give Ethyl2-(1,3,5-trimethyl-1H-pyrazol-4-yl)oct-7-ynoate as a pale yellow oil(233 mg, 17%). ESI HRMS, found 277.1919 (C₁₅H₂₅N₂O₂), MH⁺, requires277.1916. ¹H NMR (CDCl₃, 400 MHz, 300 K) δ 4.12-4.01 (2H, m), 3.66 (3H,s), 3.37 (1-H, dd, J=8.4, 7.1 Hz,), 2.17 (6H, d, J=3.8 Hz), 2.13 (2H,td, J=7.1, 2.5 Hz), 2.07-1.97 (1H, m), 1.89 (1H, t, J=2.6 Hz), 1.73-1.64(1H, m), 1.54-1.46 (2H, m,), 1.35-1.27 (2H, m), 1.18 (3H, t, J=7.1 Hz,H_(k)).

Step 4

Lithium aluminium hydride (2M in THF, 0.46 mL, 0.93 mmol) was added toEthyl 2-(1,3,5-trimethyl-1H-pyrazol-4-yl)oct-7-ynoate (233 mg, 0.843mmol) in anhydrous THF (10 mL) at 0° C. under nitrogen to give acolourless solution which was stirred at room temperature for 45 min.Water (50 μL), 15% sodium hydroxide (50 μL), followed by water (150 μL)were added at 0° C. to give a cloudy white mixture which was stirred atroom temperature for 20 min. MgSO₄ was added and the mixture was stirredfor another 20 min. The mixture was filtered and the filtrate wasconcentrated in vacuo to give2-(1,3,5-trimethyl-1H-pyrazol-4-yl)oct-7-yn-1-ol as a pale yellow oil(197 mg, ˜100%). ESI HRMS, found 235.1817 (C₁₄H₂₃N₂O), MH⁺, requires235.1810. ¹H NMR (CDCl₃, 400 MHz, 300 K) δ 3.76-3.61 (2H, m), 3.69 (3H,s), 2.76-2.68 (1H, m), 2.18 (6H, d, J=6.6 Hz), 2.14 (2H, ddd, J=9.7,4.9, 2.4 Hz), 1.91 (1H, t, J=2.7 Hz), 1.70-1.51 (2H, m), 1.52-1.43 (2H,m), 1.35-1.27 (2H, m).

Intermediate 20

6-{4-fluoro-2-[2-(1,3,5-trimethyl-1H-pyrazol-4-yl)ethoxy]phenyl}imidazo[1,2-a]pyridine-3-carbaldehydeStep 1

A solution of 6-bromoimidazo[1,2-a]pyridine-3-carbaldehyde (250 mg, 1.1mmol) was dissolved in dioxane (15 mL) and treated with4-fluoro-2-hydroxybenzene boronic acid (280 mg, 2.2 mmol) andtetrakis(triphenylphosphine) palladium(0) (128 mg), followed by asolution of potassium phosphate (590 mg, 2.7 mmol) in water (2 mL). Thereaction mixture was purged with argon then heated to 100° C. overnight,cooled to room temperature and evaporated filtered through a bed ofCelite and washed with ethylacetate. The ethylacetate layer taken driedover Na₂SO₄, and evaporated under reduced pressure. The crude productwas purified by column chromatography eluting with 2-3% MeOH in DCM togive 6-(4-fluoro-2-hydroxyphenyl)imidazo[1,2-a]pyridine-3-carbaldehyde(251 mg, 88%). ¹H NMR (400 MHz, DMSO-d₆) δ 10.52 (s, 1H), 9.95 (s, 1H),9.62 (s, 1H), 8.55 (s, 1H), 7.89 (d, 2H), 7.47 (td, 1H), 7.45 (m, 2H).

Step 2

A solution of6-(4-fluoro-2-hydroxyphenyl)imidazo[1,2-a]pyridine-3-carbaldehyde (710mg, 2.8 mmol) in dichloromethane (25 ml) was cooled to 0° C. thentreated with triethylamine (811 μL, 5.8 mmol) followed bymethanesulfonyl chloride (450 μL, 5.8 mmol). The reaction mixture wasallowed to warm to room temperature and was stirred for 18 hours beforebeing quenched with sodium bicarbonate solution (2M, 20 ml).Dichloromethane (20 ml) was added and the layers were separated. Theorganic phase was washed with water and brine then dried (Na₂SO₄) andconcentrated under reduced pressure to give the product5-fluoro-2-{3-formylimidazo[1,2-a]pyridin-6-yl}phenyl methanesulfonate(650 mg, 70%). ¹H NMR (400 MHz, DMSO-d₆) δ 9.98 (s, 1H), 9.49 (s, 1H),8.60 (s, 1H), 7.98 (d, 1H), 7.80 (d, 1H), 7.78 (td, 1H), 7.60 (dd, 1H),7.45 (td, 1H), 2.50 (s, 3H).

Step 3

According to the general method for mesyl transfer (Method B),5-fluoro-2-{3-formylimidazo[1,2-a]pyridin-6-yl}phenyl methanesulfonate(650 mg, 1.9 mmol) was reacted with4-(2-hydroxyethyl)-N,N,1,5-tetramethyl-1H-pyrazole-3-carboxamide (539mg, 3.5 mmol) and cesium carbonate (823 mg, 2.5 mmol) in DMF (18.0 mL)at 110° C. for 12 hr. The reaction mixture was extracted with EtOAc andwashed with water and brine. The combined organic parts were evaporatedunder reduced pressure to get the title intermediate. (200 mg, 26%). ¹HNMR (400 MHz, DMSO-d₆) δ 9.96 (s, 1H), 9.56 (s, 1H), 8.57 (s, 1H), 7.90(d, 1H), 7.76 (d, 1H), 7.49 (td, 1H), 7.09 (dd, 1H), 6.91 (td, 1H), 4.05(t, 2H), 3.50 (s, 3H), 2.70 (t, 2H), 2.10 (s, 3H), 2.04 (s, 3H).

Intermediate 21 tert-butylN-[2-(5-{4-fluoro-2-[2-(1,3,5-trimethyl-1H-pyrazol-4-yl)ethoxy]phenyl}-2H-indazol-3-yl)ethyl]carbamate

Step 1

A solution of 5-bromo-2-{[2-(trimethylsilyl)ethoxy]methyl}-2H-indazole(1.5 g, 4.6 mmol) was dissolved in dioxane (40 mL) and treated withbis(pinacolato)diboron (1.75 g, 6.9 mmol), potassium acetate (1.35 g,13.5 mmol) and Pd(dppf)Cl₂.DCM (374 mg). The reaction mixture was purgedwith argon then heated to 100° C. overnight, cooled to room temperatureand evaporated filtered through a bed of Celite and washed with ethylacetate. The ethyl acetate layer was dried over Na₂SO₄, and evaporatedunder reduced pressure to give5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-{[2-(trimethylsilyl)ethoxy]methyl}-2H-indazole.(1.7 g, 99%). ¹H NMR (400 MHz, DMSO-d₆) δ 8.58 (s, 1H), 8.19 (s, 1H),7.59 (d, 1H), 7.47 (d, 1H), 5.73 (s, 2H), 3.60 (t, 2H), 1.30 (s, 12H),0.85 (t, 2H), −0.07 (s, 9H).

Step 2

A solution of5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-{[2-(trimethylsilyl)ethoxy]methyl}-2H-indazole(1.0 g, 2.67 mmol) and4-[2-(2-bromo-5-fluorophenoxy)ethyl]-1,3,5-trimethyl-1H-pyrazole (0.87g, 2.67 mmol) in dioxane (20 mL) was treated with potassium carbonate(1.1 g, 8.0 mmol) dissolved in water (5 mL. The mixture was degassedwith argon for 15 min before addition of Pd(dppf)C12.DCM (218 mg) Thereaction mixture was heated at 100° C. for 16 hr, cooled to RT, filteredthrough Celite and the filtrate was diluted with EtOAc. The organiclayer was washed with water, brine, dried over Na₂SO₄ and concentratedunder reduced pressure. The crude product was purified by Combiflash (40g silica column, 50% EtOAc-Hexane) to afford the product5-{4-fluoro-2-[2-(1,3,5-trimethyl-1H-pyrazol-4-yl)ethoxy]phenyl}-2-{[2-(trimethylsilyl)ethoxy]methyl}-2H-indazole(750 mg, 57%). ¹H NMR (400 MHz, DMSO-d₆) δ 8.51 (s, 1H), 7.68 (s, 1H),7.60 (d, 1H), 7.34-7.27 (m, 2H), 6.99 (dd, 1H), 6.83 (td, 1H), 5.76 (s,2H), 4.00 (t, 2H), 3.61 (t, 2H), 3.52 (s, 3H), 2.66 (t, 2H), 1.88 (s,6H), 0.87 (t, 2H), −0.04 (s, 9H).

Step 3

A stirred solution of5-{4-fluoro-2-[2-(1,3,5-trimethyl-1H-pyrazol-4-yl)ethoxy]phenyl}-2-{[2-(trimethylsilyl)ethoxy]methyl}-2H-indazole(750 mg, 1.5 mmol) in THF (14 mL) was treated with n-BuLi solution (2.4Min hexane, 1.26 mL, 3 mmol) dropwise at −78° C. The reaction mixture wasstirred at −78° C. for 30 min. Then DMF (0.468 mL, 6.0 mmol) was addedat −78° C. The reaction mixture was allowed to warm up to 0° C. andstirred for 2 hr. The reaction mixture was quenched with NH₄Cl solutionand extracted with EtOAc. The organic layer was washed with brine, driedover Na₂SO₄ and concentrated under reduced pressure to give5-{4-fluoro-2-[2-(1,3,5-trimethyl-1H-pyrazol-4-yl)ethoxy]phenyl}-2-{[2-(trimethylsilyl)ethoxy]methyl}-2H-.indazole-3-carbaldehyde (750 mg, 95%). ¹H NMR (400 MHz, DMSO-d₆) δ 10.40(s, 1H), 8.17 (s, 1H), 7.86 (d, 1H), 7.48 (d, 1H), 7.40 (dd, 2H), 7.04(dd, 1H), 6.86 (td, 1H), 6.16 (s, 2H), 4.02 (t, 2H), 3.63 (t, 2H), 3.60(s, 3H), 2.66 (t, 2H), 1.98 (s, 3H), 1.84 (s, 3H), 0.85 (t, 2H), −0.07(s, 9H).

Step 4

A solution of5-{4-fluoro-2-[2-(1,3,5-trimethyl-1H-pyrazol-4-yl)ethoxy]phenyl}-2-{[2-(trimethylsilyl)ethoxy]methyl}-2H-indazole-3-carbaldehyde(750 mg, 1.43 mmol) in methanol (11 mL) was treated with sodiumborohydride (109 mg, 2.9 mmol) at 0° C. and stirred at 0° C. for 1.5 h.The reaction mixture was quenched with NaHCO₃ solution and extractedwith DCM. The organic layer was dried over Na₂SO₄ and concentrated underreduced pressure to give5-{4-fluoro-2-[2-(1,3,5-trimethyl-1H-pyrazol-4-yl)ethoxy]phenyl}-2-{[2-(trimethylsilyl)-ethoxy]methyl}-2H-indazol-3-yl)methanol(750 mg, 99%). ¹H NMR (400 MHz, DMSO-d₆) δ 7.73 (s, 1H), 7.56 (d, 1H),7.30-7.26 (m, 2H), 6.98 (dd, 1H), 6.84 (td, 1H), 5.80 (s, 2H), 5.55 (t,1H), 4.95 (d, 2H), 4.02 (t, 2H), 3.59 (t, 2H), 3.51 (s, 3H), 2.66 (t,2H), 1.96 (s, 3H), 1.89 (s, 3H), 0.86 (t, 2H), −0.06 (s, 9H).

Step 5

A solution of5-{4-fluoro-2-[2-(1,3,5-trimethyl-1H-pyrazol-4-yl)ethoxy]phenyl}-2-{[2-(trimethylsilyl)-ethoxy]methyl}-2H-indazol-3-yl)methanol(50 mg, 0.095 mmol) in thionyl chloride (2 mL) was heated to 80° C. for3 h. The reaction was concentrated under reduced pressure. The crudeproduct was neutralized with NaHCO₃ solution and extracted with EtOAc.The organic layer was dried over Na₂SO₄ and concentrated under reducedpressure to give3-(chloromethyl)-5-{4-fluoro-2-[2-(1,3,5-trimethyl-1H-pyrazol-4-yl)ethoxy]phenyl}-2H-indazole(39 mg, 99%). ¹H NMR (400 MHz, DMSO-d₆) δ 7.87 (s, 1H), 7.72 (d, 1H),7.48 (d, 1H), 7.33 (d, 1H), 7.00 (dd, 1H), 6.87 (td, 1H), 5.73 (s, 2H),5.15 (s, 2H), 4.01 (t, 2H), 3.57 (s, 3H), 2.67 (t, 2H), 1.92 (s, 3H),1.87 (s, 3H).

Step 6

A solution of3-(chloromethyl)-5-{4-fluoro-2-[2-(1,3,5-trimethyl-1H-pyrazol-4-yl)ethoxy]phenyl}-2H-indazole(354 mg, 0.86 mmol) in DMF (5 mL) was treated with sodium cyanide (126mg, 2.6 mmol) and the reaction mixture was heated to 100° C. for 3 h.The reaction mixture was cooled to rt, diluted with EtOAc and washedwith water. The organic layer was dried over Na₂SO₄ and concentratedunder reduced pressure. The crude product was purified through columnchromatography on silica by elution with MeOH-DCM (4:96) to afford afraction containing2-(5-{4-fluoro-2-[2-(1,3,5-trimethyl-1H-pyrazol-4-yl)ethoxy]phenyl}-2H-indazol-3-yl)acetonitrile,which was taken onto the next step without purification.

Step 7

A solution of2-(5-{4-fluoro-2-[2-(1,3,5-trimethyl-1H-pyrazol-4-yl)ethoxy]phenyl}-2H-indazol-3-yl)acetonitrile(100 mg, 0.25 mmol) in methanol (2.5 mL) was treated with Boc₂O (0.114mL, 0.50 mmol) and NiCl₂.6H₂O (5.9 mg, 0.025 mmol) followed byportionwise addition of NaBH₄ (65 mg, 1.73 mmol) at 0° C. The reactionmixture was allowed to stirred at RT for 16 h. The reaction mixture wasquenched with NaHCO₃ solution and extracted with DCM. The organic layerwas dried over Na₂SO₄ and concentrated under reduced pressure. The crudewas purified over prep TLC (3% MeOH in DCM) to give tert-butylN-[2-(5-{4-fluoro-2-[2-(1,3,5-trimethyl-1H-pyrazol-4-yl)ethoxy]phenyl}-2H-indazol-3-yl)ethyl]carbamate(27 mg, 21%). LC-MS rt 3.33 min, MH⁺ 508.

Intermediate 22 tert-butylN-[(tert-butoxy)carbonyl]-N-{2-[6-(4-fluoro-2-hydroxyphenyl)imidazo[1,2-a]pyridin-3-yl]ethyl}carbamateStep 1

A solution of 2-{6-bromoimidazo[1,2-a]pyridin-3-yl}ethylamine (1.4 g,5.8 mmol) in DCM (20 ml) was cooled at 0° C. and treated withtriethylamine (2.4 mL, 17.5 mmol) and (Boc)₂O (3.35 mL, 14.6 mmol). Thereaction mixture was stirred at rt for 16 hr, diluted with DCM, andwashed with sat. NaHCO₃, water and brine, dried over sodium sulphate andevaporated under reduced pressure. The crude product was separated bycolumn chromatography on silica eluting with 4% MeOH in DCM to givetert-butyl N-(2-{6-bromoimidazo[1,2-a]pyridin-3-yl}ethyl)carbamate (1.0g, 50%) ¹H NMR (400 MHz, DMSO-d₆) δ 8.64 (s, 1H), 7.51 (d, 1H), 7.41 (s,1H), 7.30 (d, 1H), 6.95 (t, 1H), 3.26 (t, 2H), 3.00 (t, 2H), 1.43 (s,9H) and tert-butylN-[(tert-butoxy)carbonyl]-N-{2-[6-bromo-imidazo[1,2-a]pyridin-3-yl]ethyl}carbamate(900 mg, 35%). ¹H NMR (400 MHz, DMSO-d₆) δ 8.63 (s, 1H), 7.53 (d, 1H),7.35-7.30 (m, 2H), 3.78 (t, 2H), 3.18 (t, 2H), 1.31 (s, 18H).

Step 2

A solution of tert-butylN-[(tert-butoxy)carbonyl]-N-{2-[6-bromo-imidazo[1,2-a]pyridin-3-yl]ethyl}carbamate(900 mg, 2.0 mmol) was dissolved in dioxane (20 mL) and treated with4-fluoro-2-hydroxybenzene boronic acid (637 mg, 4.1 mmol) followed by asolution of potassium phosphate (1.08 g, 5.1 mmol) in water (5 mL). Thereaction mixture was purged with argon before addition oftetrakis(triphenylphosphine) palladium(0) (236 mg) and the mixture wasthen heated to 100° C. for 16 hr, cooled to room temperature andfiltered through a bed of Celite and washed with ethyl acetate. Theethyl acetate layer taken dried over Na₂SO₄, and evaporated underreduced pressure. The crude product was purified by columnchromatography eluting with 5% MeOH in DCM to give tert-butylN-[(tert-butoxy)carbonyl]-N-{2-[6-(4-fluoro-2-hydroxyphenyl)imidazo[1,2-a]pyridin-3-yl]ethyl}carbamate(250 mg, 26%). ¹H NMR (400 MHz, DMSO-d₆) δ 10.27 (s, 1H), 8.35 (s, 1H),7.65 (d, 1H), 7.53 (d, 1H), 7.41-7.30 (m, 2H), 6.75 (td, 1H), 3.80 (t,2H), 3.25 (t, 3H), 1.28 (s, 18H).

Intermediate 23 tert-butylN-(2-{6-[4-fluoro-2-(methanesulfonyloxy)phenyl]imidazo[1,2-a]pyridin-3-yl}ethyl)carbamateStep 1

A solution of 2-{6-bromoimidazo[1,2-a]pyridin-3-yl}ethylamine (350 mg,1.46 mmol) in DCM (10 ml) was cooled at 0° C. and treated withtriethylamine (0.61 mL, 4.4 mmol) and (Boc)₂O (0.84 mL, 3.6 mmol). Thereaction mixture was stirred at rt for 16 hr, diluted with DCM, andwashed with sat. NaHCO₃, water and brine, dried over sodium sulphate andin 100-200 silica eluting with 4% MeOH in DCM to give tert-butylN-(2-{6-bromoimidazo[1,2-a]pyridin-3-yl}ethyl)carbamate (490 mg, 99%).¹H NMR (400 MHz, DMSO-d₆) δ 8.64 (s, 1H), 7.51 (d, 1H), 7.41 (s, 1H),7.30 (d, 1H), 6.95 (t, 1H), 3.26 (t, 2H), 3.00 (t, 2H), 1.43 (s, 9H).

Step 2

A solution of tert-butylN-(2-{6-bromoimidazo[1,2-a]pyridin-3-yl}ethyl)carbamate (1.4 g, 4.2mmol) was dissolved in dioxane/water (5:1, 15 mL) and treated with4-fluoro-2-hydroxybenzene boronic acid (1.3 g, 8.2 mmol) andtetrakis(triphenylphosphine) palladium(0) (476 mg, 0.4 mmol), followedby a solution of potassium phosphate (2.1 g, 10.3 mmol) in water (2 mL).The reaction mixture was purged with argon then heated to 100° C. for 16hr, cooled to room temperature and filtered through a bed of Celite andwashed with ethyl acetate. The ethyl acetate layer taken dried overNa₂SO₄, and evaporated under reduced pressure. The crude product waspurified by column chromatography eluting with 5% MeOH in DCM to givetert-butylN-{2-[6-(4-fluoro-2-hydroxyphenyl)imidazo[1,2-a]pyridin-3-yl]ethyl}carbamate(250 mg, 57%), which was taken onto the next step without further.purification.

Step 3

A solution of tert-butylN-{2-[6-(4-fluoro-2-hydroxyphenyl)imidazo[1,2-a]pyridin-3-yl]ethyl}carbamate(250 mg, 0.67 mmol) in dichloromethane (10 mL) was cooled to 0° C. thentreated with triethylamine (235 μL, 1.7 mmol) followed bymethanesulfonyl chloride (63 μL, 0.68 mmol). The reaction mixture wasallowed to warm to room temperature and was stirred for 4 hr. Thereaction mixture was then diluted with DCM, and washed with sat. NaHCO₃,water and brine, dried over Na₂SO₄ and concentrated under reducedpressure. The crude was then purified by column chromatography elutingwith 3% MeOH in DCM to give tert-butylN-(2-{6-[4-fluoro-2-(methanesulfonyloxy)phenyl]imidazo[1,2-a]pyridin-3-yl}ethyl)carbamate(170 mg, 56%). ¹H NMR (400 MHz, DMSO-d₆) δ 8.44 (s, 1H), 7.72 (td, 1H),7.61 (d, 1H), 7.51 (dd, 1H), 7.45-7.39 (m, 2H), 7.32 (d, 1H), 6.97 (td,1H), 4.10 (t, 1H), 3.30-3.20 (m, 5H), 3.03 (t, 2H), 1.30 (s, 9H).

Intermediate 24 tert-butylN-{[6-(4-fluoro-2-hydroxyphenyl)imidazo[1,2-a]pyridin-3-yl]methyl}-N-methylcarbamateStep 1

A solution of 2-{6-bromoimidazo[1,2-a]pyridin-3-yl}-N-methyl-methylamine(1.4 g, 5.8 mmol) in DCM (20 ml) was cooled at 0° C. and treated withtriethylamine (1.62 mL, 8.8 mmol) and (Boc)₂O (2.0 mL, 8.8 mmol). Thereaction mixture was stirred at rt for 16 hr, diluted with DCM, andwashed with sat. NaHCO₃, water and brine, dried over sodium sulphate andevaporated under reduced pressure. The crude product was purified bycolumn chromatography on silica eluting with 3% MeOH in DCM to givetert-butylN-({6-bromoimidazo[1,2-a]pyridin-3-yl}methyl)-N-methylcarbamate (1.30 g,65%). ¹H NMR (400 MHz, DMSO-d₆) δ 8.70 (br.s, 1H), 7.62 (s, 1H), 7.59(d, 1H), 7.38 (d, 1H), 4.77 (s, 2H), 2.67 (s, 3H), 1.41 (s, 9H).

Step 2

A solution of tert-butylN-({6-bromoimidazo[1,2-a]pyridin-3-yl}methyl)-N-methylcarbamate (1.1 g,3.2 mmol) was dissolved in dioxane (8 mL) and treated with4-fluoro-2-hydroxybenzene boronic acid (1.0 g, 6.5 mmol) and potassiumphosphate (1.7 g, 3.3 mmol) in water (2 mL). The reaction mixture waspurged with argon for 5 min, before addition of tetrakis(triphenylphosphine) palladium(0) (374 mg). The reaction mixture washeated to 100° C. under nitrogen overnight, cooled to room temperatureand filtered through a bed of Celite, which was washed with ethylacetate. The ethyl acetate layer was dried over Na₂SO₄, and evaporatedunder reduced pressure. The crude product was purified by columnchromatography eluting with 5% MeOH in DCM to give tert-butylN-{[6-(4-fluoro-2-hydroxyphenyl)imidazo[1,2-a]pyridin-3-yl]methyl}-N-methylcarbamate(1.0 g, 83%). ¹H NMR (400 MHz, CDCl₃) δ 8.50 (s, 1H), 7.59 (d, 1H), 7.55(s, 1H), 7.37 (d, 1H), 7.20 (td, 1H), 6.73 (dd, 1H), 6.67 (td, 1H), 4.74(s, 2H), 2.73 (s, 3H), 1.42 (s, 9H).

Intermediate 25 tert-butylN-{[6-(4-fluoro-2-hydroxyphenyl)imidazo[1,2-a]pyridin-3-yl]ethyl}-N-methylcarbamateStep 1

A solution of tert-butyl(2-(6-bromoimidazo[1,2-a]pyridin-3-yl)ethyl)carbamate (1.4 g, 4.1 mmol)in THF (15 mL) was cooled at 0° C. and treated with sodium hydride (50%dispersion, 119 mg, 4.9 mmol. The reaction mixture was stirred at 0° C.for 30 min before dropwise addition of iodomethane (0.31 mL, 4.9 mmol).The reaction mixture was warmed to rt and stirred for a further 16 hr,then diluted with ethyl acetate, washed with water and brine, dried oversodium sulphate and concentrated under reduced pressure. The crudeproduct was purified by column chromatography on silica eluting with 3%MeOH in DCM to give tert-butylN-({6-bromoimidazo[1,2-a]pyridin-3-yl}ethyl)-N-methylcarbamate (1.2 g,82%). ¹H NMR (400 MHz, DMSO-d₆) δ 8.72 (br.s, 1H), 7.57 (s, 1H), 7.39(d, 1H), 7.31 (d, 1H), 3.47 (t, 2H), 3.16 (t, 2H), 2.78 (s, 3H), 0.99(s, 9H).

Step 2

A solution of tert-butylN-({6-bromoimidazo[1,2-a]pyridin-3-yl}ethyl)-N-methylcarbamate (1.2 g,3.4 mmol) was dissolved in dioxane (13 mL) and treated with4-fluoro-2-hydroxybenzene boronic acid (1.05 g, 6.8 mmol) followed by asolution of potassium phosphate (1.8 g, 8.5 mmol) in water (2 mL). Thereaction mixture was purged with argon before addition oftetrakis(triphenylphosphine) palladium(0) (392 mg), then heated to 100°C. overnight, cooled to room temperature and evaporated filtered througha bed of Celite and washed with ethyl acetate. The ethyl acetate layertaken dried over Na₂SO₄, and evaporated under reduced pressure. Thecrude product was purified by column chromatography eluting with 5% MeOHin DCM to give tert-butylN-{[6-(4-fluoro-2-hydroxyphenyl)imidazo[1,2-a]pyridin-3-yl]ethyl}-N-methylcarbamate(1.0 g, 76%). ¹H NMR (400 MHz, DMSO-d₆) δ 10.29 (s, 1H), 8.42 (s, 1H),7.80-7.55 (m, 2H), 7.50-7.40 (m, 3H), 6.80-6.70 (m, 2H), 3.49 (t, 2H),3.15 (t, 2H), 2.80 (s, 3H), 1.04 (s, 9H).

Intermediate 266-(3-Fluoro-2-(2-(1,3,5-trimethyl-1H-pyrazol-4-yl)ethoxy)phenyl)imidazo[1,2-a]pyridine-3-carbaldehydeStep 1

To a stirred solution of 6-bromoimidazo[1,2-a]pyridine-3-carbaldehyde(1.2 g, 5.30 mmol) in dioxane:water (4:1, 20 mL),(3-fluoro-2-hydroxyphenyl)boronic acid (1.25 g, 8.0 mmol,) and K₃PO₄(2.83 g, 13.33 mmol) was added, and the reaction mixture was purged withargon for 15 min. Tetrakis(triphenyl phosphine)palladium(0) (0.617 g,0.53 mmol) was added and the reaction mixture was stirred at 100° C. for5 h. The reaction mixture was filtered through a pad of Celite andwashed the filtration cake with 10% MeOH/DCM (2×15 mL). The combinedfiltrate was evaporated to dryness under reduced pressure. The crudeproduct was purified column chromatography to afford6-(3-fluoro-2-hydroxyphenyl)imidazo[1, 2-a]pyridine-3-carbaldehyde (720mg, 51%) as a light yellow solid.

¹H NMR (400 MHz, CDCl₃) δ 9.98 (s, 1H), 9.77 (s, 1H), 8.36 (s, 1H), 7.86(s, 1H), 7.71-7.50 (m, 2H), 7.20-7.12 (m, 2H), 7.02-6.97 (m, 1H).

Step 2

To a stirred solution of 6-(3-fluoro-2-hydroxyphenyl)imidazo[1,2-a]pyridine-3-carbaldehyde (0.6 g, 2.34 mmol) and triphenylphosphine(1.23 g, 4.68 mmol) in THF (15 mL) was added dropwise a solution of2-(1,3,5-trimethyl-1H-pyrazol-4-yl)ethanol (720 mg, 4.68 mmol) in THE(10 mL). The reaction mixture was cooled to 0° C. and was addeddi-isopropyl azodicarboxylate (0.92 mL, 4.68 mmol). The reaction mixturewas allowed to warm to room temperature, stirred overnight andconcentrated under reduced pressure. The crude was purified by columnchromatography to afford6-(3-fluoro-2-(2-(1,3,5-trimethyl-1H-pyrazol-4-yl)ethoxy)phenyl)imidazo[1,2-a]pyridine-3-carbaldehyde (440 mg, 48%) as an off-white solid.

¹H NMR (400 MHz, CDCl₃) δ 9.97 (s, 1H), 9.61 (s, 1H), 8.36 (s, 1H),7.79-7.64 (m, 2H), 7.23-7.08 (m, 3H), 3.93 (t, J=7.4 Hz, 2H), 3.60 (s,3H), 2.65 (t, J=7.5 Hz, 2H), 2.01 (s, 3H), 1.94 (s, 3H).

Intermediate 27 tert-butyl (2-(6-(3-fluoro-2-hydroxyphenyl) imidazo [1,2-a] pyridin-3-yl) ethyl) carbamate

To a stirred solution of tert-butyl(2-(6-bromoimidazo[1,2-a]pyridin-3-yl)ethyl)carbamate (750 mg, 2.20mmol) in dioxane/water (3:1, 14 mL), (3-fluoro-2-hydroxyphenyl)boronicacid (510 mg, 3.30 mmol) and K₃PO₄ (1.17 g, 5.50 mmol) was added anddegassed with argon for 15 min. Pd(PPh₃)₄ (250 mg, 0.22 mmol) was addedto the reaction mixture and stirred at 90° C. for 5 h. The progress ofthe reaction was monitored by TLC. After completion of the reaction, thereaction mixture was filtered through Celite and washed with 10% MeOH inDCM. The reaction mixture was concentrated under reduced pressure andpurified by column chromatography to afford tert-butyl(2-(6-(3-fluoro-2-hydroxyphenyl) imidazo [1, 2-a] pyridin-3-yl) ethyl)carbamate (600 mg, 76%). ¹H NMR (400 MHz, DMSO-d6) δ 9.80 (s, 1H), 8.42(s, 1H), 7.69-7.48 (m; 1H), 7.42 (t, J=4.8 Hz, 2H), 7.27-7.21 (m, 2H),7.02-6.87 (m, 2H), 3.27 (t, J=6.7 Hz, 2H), 3.03 (q, J=7.6, 7.2 Hz, 2H),1.31 (s, 9H).

Intermediate 28 tert-butyl(2-(6-(3-fluoro-2-hydroxyphenyl)imidazo[1,2-a]pyridin-3-yl)ethyl)(N-methyl) carbamate

A solution of tert-butyl(2-(6-bromoimidazo[1,2-a]pyridin-3-yl)ethyl)(N-methyl)carbamate(Intermediate 23 Step 1, 180 mg, 0.50 mmol) in dioxane and water (4:2,10 mL), (3-fluoro-2-hydroxyphenyl)boronic acid (110 mg, 0.76 mmol) andK₃PO₄ (265 mg, 1.25 mmol) was degassed with argon for 15 min. Pd (PPh₃)₄(57 mg, 0.05 mmol) was added to the reaction mixture and stirred at 90°C. for 5 hr. The progress of the reaction was monitored by TLC. Aftercompletion of the reaction, the reaction mixture was filtered throughcelite and washed with EtOAc followed by water. The reaction mixture wasextracted with EtOAc. The combined organic layer were washed with brine,dried over anhydrous Na₂SO₄ and concentrated under reduced pressure. Theresidue was purified by column chromatography to afford the titleintermediate (140 mg, 72%) as an off white solid.

Intermediate 29 tert-butyl (2-(6-(3,4-difluoro-2-hydroxyphenyl) imidazo[1, 2-a] pyridin-3-yl) ethyl) carbamate

A solution of tert-butyl(2-(6-bromoimidazo[1,2-a]pyridin-3-yl)ethyl)carbamate (90 mg, 0.23 mmol)in dioxane/water (3:1, 14 mL) was treated with2,3-difluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (71mg, 0.46 mmol) and K₃PO₄ (1.17 g, 5.50 mmol). The mixture was degassedwith argon for 15 min before addition of Pd(PPh₃)₄ (250 mg, 0.22 mmol)and the reaction mixture was then heated to 90° C. for 5 hr. Thereaction mixture was filtered through Celite and washed with 10% MeOH inDCM. The reaction mixture was concentrated under reduced pressure andpurified by column chromatography to afford tert-butyl(2-(6-(3,4-difluoro-2-hydroxyphenyl) imidazo [1, 2-a] pyridin-3-yl)ethyl) carbamate (38 mg, 31%). ¹H NMR (400 MHz, CDCl₃) δ 8.06 (s, 1H),7.63 (d, J=9.3 Hz, 1H), 7.51 (s, 1H), 7.25 (s, 1H), 7.12-7.05 (m, 1H),7.05-6.94 (m, 1H), 5.31 (s, 2H), 3.96 (t, J=7.1 Hz, 1H), 3.69 (d, J=9.6Hz, 1H), 3.52 (d, J=6.0 Hz, 3H), 3.11-3.03 (m, 2H

Preparation of Examples 1-108 Example 1

N,N-dimethyl-1-(5-(2-(pyridin-3-ylmethoxy)phenyl)-1H-indazol-3-yl)methanamineStep 1

According to the general method for mesyl transfer (Method A),intermediate 1 (43 mg, 0.1 mmol was reacted with 3-pyridinemethanol (9.7μL, 0.1 mmol) and sodium t-butoxide (9.6 mg, 0.1 mmol) in acetonitrile(0.5 ml). Partial purification by column chromatography provided the THPprotected indazole. δ_(H)/ppm ¹H NMR (400 MHz, Chloroform-d) δ 8.61 (d,J=2.2 Hz, 1H), 8.53 (dd, J=4.9, 1.6 Hz, 1H), 8.01 (d, J=1.5 Hz, 1H),7.65-7.59 (m, 2H), 7.58 (s, 1H), 7.42 (dd, J=7.5, 1.8 Hz, 1H), 7.32 (td,J=7.9, 1.9 Hz, 1H), 7.23 (dd, J=7.9, 4.8 Hz, 1H), 7.11 (d, J=7.5 Hz,1H), 7.07 (d, J=8.4 Hz, 1H), 5.71 (dd, J=9.8, 2.6 Hz, 1H), 5.09 (s, 2H),4.09 (s, 1H), 3.81 (s, 2H), 3.77 (td, J=11.6, 3.1 Hz, 1H), 2.67-2.51 (m,1H), 2.29 (s, 6H), 2.16 (ddd, J=8.8, 4.5, 2.3 Hz, 1H), 2.11-2.07 (m,1H), 1.84-1.71 (m, 2H), 1.65 (dt, J=9.3, 3.1 Hz, 1H).

Step 2

According to the general method for THP deprotection (Method A), theproduct from Step 1 was used to prepare the title compound as acolourless oil (14.2 mg, yield over 2 steps: 40%) LC-MS rt 10.1 min MH⁺359.

δ_(H)/ppm ¹H NMR (400 MHz, Chloroform-d) δ 8.64 (d, J=2.1 Hz, 1H), 8.56(dd, J=5.0, 1.5 Hz, 1H), 8.00 (d, J=1.2 Hz, 1H), 7.64 (ddd, J=8.6, 5.6,1.8 Hz, 2H), 7.49-7.42 (m, 2H), 7.36 (td, J=7.8, 1.8 Hz, 1H), 7.25 (dd,J=7.8, 4.8 Hz, 1H), 7.14 (t, J=7.7 Hz, 1H), 7.10 (d, J=8.3 Hz, 1H), 5.11(s, 2H), 3.88 (s, 2H), 2.36 (s, 6H).

The following compounds were made by analogous methods:

SM General Procedure intermediate Mesyl THP Reductive Boc Ex NoStructure N^(o) method method a mination Deprotection YieldCharacterisation 2

1 A A 11.8 mg, yield over 2 steps: 32% LC-MS rt 12.8 min MH⁺ 372 ¹H NMR(400 MHz, Chloroform-d) δ 7.99 (d, J = 1.2 Hz, 1H), 7.53 (dd, J = 8.5,1.6 Hz, 1H), 7.46-7.39 (m, 2H), 7.33 (td, J = 7.9,1.9 Hz, 1H), 7.24 (td,J = 5.1, 4.7, 2.2 Hz, 3H), 7.17 (dd, J = 7.3, 2.1 Hz, 2H), 7.07 (t, J =7.4 Hz, 1H), 7.01 (d, J = 8.2 Hz, 1H), 4.22 (t, J = 6.8 Hz, 2H), 3.90(s, 2H), 3.04 (t, J = 6.8 Hz, 2H), 2.37 (s, 6H). N,N-dimethyl-1-(5-(2-phenethoxyphenyl)-1H- indazol-3-yl)methanamine 3

1 A A 15.9 mg, yield over 2 steps: 37% LC-MS rt 10.9 min MH⁺ 409 ¹H NMR(400 MHz, Chloroform-d) δ 8.84 (d, J = 4.5 Hz, 1H), 8.17 (d, J = 8.4 Hz,1H), 8.04 (d, J = 1.3 Hz, 1H), 7.91 (d, J = 8.2 Hz, 1H), 7.74 (dd, J =8.3, 6.9 Hz, 1H), 7.66 (dd, J = 8.7, 1.6 Hz, 1H), 7.54 (t, J = 7.6 Hz,1H), 7.51- 7.44 (m, 3H), 7.38 (td, J = 7.8, 1.8 Hz, 1H), 7.20-7.12 (m,2H), 5.58 (s, 2H), 3.85 (s, 2H), 2.32 (s, 6H).N,N-dimethyl-1-(5-(2-(quinolin- 4-ylmethoxy)phenyl)-1H-indazol-3-yl)methanamine 4

1 A A 3.3 mg, yield over 2 steps: 7.7% LC-MS rt 8.8 min MH⁺ 373 ¹H NMR(400 MHz, Chloroform-d) δ 8.47 (dd, J = 4.9, 1.7 Hz, 1H), 8.46 (d, J =2.3 Hz, 1H), 7.92 (d, J = 1.1 Hz, 1H), 7.50 (d, J = 8.7 Hz, 1H),7.46-7.38 (m, 3H), 7.33 (td, J = 7.9, 1.9 Hz, 1H), 7.13-7.04 (m, 2H),6.99 (d, J = 8.1 Hz, 1H), 4.22 (t, J = 6.2 Hz, 2H), 3.93 (s, 2H), 3.02(t, J = 6.2 Hz, 2H), 2.40 (s, 6H). N,N-dimethyl-1-(5-(2-(2-(pyridin-3-yl)ethoxy)phenyl)- 1H-indazol-3-yl)methanamine 5

1 A A 10.9 mg, yield over 2 steps: 30% LC-MS rt 7.7 min MH⁺ 362 ¹H NMR(400 MHz, Methanol-d4) δ 7.87 (d, J = 1.2 Hz, 1H), 7.52 (d, J = 8.6 Hz,1H), 7.45-7.35 (m, 3H), 7.41-7.31 (m, 1H), 7.10-7.00 (m, 2H), 6.95 (s,1H), 6.84 (s, 1H), 4.32 (s, 2H), 4.24 (s, 2H), 3.92 (s, 2H), 2.35 (s,6H). 1-(5-(2-(2-(1H-imidazol-1- yl)ethoxy)phenyl)-1H-indazol-3-yl)-N,N-dimethylmethanamine 6

1 C A 17.2 mg, yield over 2 steps: 10% LC-MS rt 2.2 min (50-98) MH⁺ 358¹H NMR (400 MHz, Chloroform-d) δ 8.07 (d, J = 1.3 Hz, 1H), 7.67 (dd, J =8.8, 1.8 Hz, 1H), 7.47 (d, J = 8.6 Hz, 1H), 7.44 (dd, J = 7.8, 1.8 Hz,1H), 7.40-7.27 (m, 7H), 7.10 (t, J = 7.5 Hz, 3H), 5.12 (s, 2H), 3.91 (s,2H), 2.36 (s, 6H). N,N-dimethyl-1-(5-(2- benzyloxyphenyl)-1H-indazol-3-yl)methanamine 7

2 2 A B A B 5.9 mg, yield over 2 steps: 14% 31 mg, 42% LC-MS rt 11.1 minMH⁺ 422 ¹H NMR (400 MHz, Chloroform-d) δ 7.92 (s, 1H), 7.46 (d, J = 1.3Hz, 2H), 7.31 (dd, J = 8.5, 6.9 Hz, 1H), 6.75 (td, J = 8.1, 2.4 Hz, 1H),6.69 (dd, J = 11.0, 2.5 Hz, 1H), 3.95 (t, J = 7.1 Hz, 2H), 3.90 (s, 2H),3.64 (s, 3H), 2.75 (t, J = 7.1 Hz, 2H), 2.36 (s, 6H), 2.07 (s, 3H), 1.92(s, 3H). ″data as above″ 1-(5-(4-fluoro-2-(2-(l,3,5-trimethyl-1H-pyrazol-4- yl)ethoxy)phenyl)-1H-indazol-3-yl)-N,N-dimethylmethanamine 8

2 A A 10.0 mg, yield over 2 steps: 25% LC-MS rt 8.9 min MH⁺ 391 ¹H NMR(400 MHz, Chloroform-d) δ 8.48 (dd, J = 4.9, 1.7 Hz, 1H), 8.44 (d, J =2.2 Hz, 1H), 7.84 (d, J = 2.1 Hz, 1H), 7.48 (d, J = 8.7 Hz, 1H), 7.41(dt, J = 7.8, 2.0 Hz, 1H), 7.35-7.28 (m, 2H), 7.08 (dd, J = 7.8, 4.7 Hz,1H), 6.75 (td, J = 8.3, 2.5 Hz, 1H), 6.69 (dd, J = 10.8, 2.5 Hz, 1H),4.18 (t, J = 6.1 Hz, 2H), 3.91 (d, J = 2.4 Hz, 2H), 3.01 (t, J = 6.1 Hz,2H), 2.38 (s, 6H). N,N-dimethyl-1-(5-(4-fluoro-2- (2-(pyridin-3-yl)ethoxy)phenyl)-1H-indazol- 3-yl)methanamine 9

2 A A 14.2 mg, yield over 2 steps: 40% LC-MS rt 9.5 min MH⁺ 377 ¹H NMR(400 MHz, Chloroform-d) δ 8.63 (d, J = 2.0 Hz, 1H), 8.56 (dd, J = 4.8,1.7 Hz, 1H), 7.93 (d, J = 1.6 Hz, 1H), 7.62 (dt, J = 7.9, 2.1 Hz, 1H),7.54 (dd, J = 8.8, 1.5 Hz, 1H), 7.41 (d, J = 8.6 Hz, 1H), 7.37 (dd, J =9.2, 6.7 Hz, 1H), 7.24 (dd, J = 7.9, 4.9 Hz, 1H), 6.82 (ddd, J = 10.7,5.1, 2.5 Hz, 2H), 5.08 (s, 2H), 3.86 (s, 2H), 2.34 (s, 6H).N,N-dimethyl-1-(5-(4-fluoro-2- (pyridin-3-ylmethoxy)phenyl)-1H-indazol-3-yl)methanamine 10

2 A A 15.1 mg, yield over 2 steps: 40% LC-MS rt 4.0 min MH⁺ 380 . ¹H NMR(400 MHz, Methanol-d4) δ 7.88- 7.79 (m, 1H), 7.53 (d, J = 8.6 Hz, 1H),7.42 (d, J = 1.5 Hz, 1H), 7.35 (dd, J = 7.4, 1.5 Hz, 2H), 6.95 (s, 1H),6.87 (d, J = 11.0 Hz, 1H), 6.84 (s, 1H), 6.80 (td, J = 8.3, 2.5 Hz, 1H),4.34 (dd, J = 5.3, 3.9 Hz, 2H), 4.30-4.23 (m, 2H), 3.91 (s, 2H), 2.33(s, 6H). 1-(5-(2-(4-fluoro-2-(1H- imidazol-1-yl)ethoxy)phenyl)-1H-indazol-3-yl)-N,N- dimethylmethanamine 11

2 A A 11.9 mg, yield over 2 steps: 28% LC-MS rt 9.4 min MH⁺ 430. ¹H NMR(400 MHz, Chloroform-d) δ 7.81 (d, J = 1.2 Hz, 1H), 7.72 (s, 1H), 7.60(d, 1H), 7.36-7.17 (m, 5H), 6.77 (d, J = 2.4 Hz, 1H), 6.64 (dd, J =10.6, 2.5 Hz, 1H), 4.50 (t, 1H), 4.28 (t, 2H), 4.04 (s, 2H), 2.48 (s,6H). 1-(5-(2-(2-(1H- benzo[d]imidazol-1-yl)ethoxy)-4-fluorophenyl)-1H-indazol-3- yl)-N,N-dimethylmethanamine 12

2 A A 3.7 mg, yield over 2 steps: 10% LC-MS rt 9.9 min MH⁺ 381. ¹H NMR(400 MHz, Chloroform-d) δ 7.99 (s, 1H), 7.83 (d, J = 2.7 Hz, 2H), 7.51(d, J = 8.4 Hz, 2H), 7.34-7.29 (m, 1H), 7.13 (dd, J = 8.5, 1.7 Hz, 1H),6.79 (d, J = 2.4 Hz, 1H), 6.72-6.62 (m, 1H), 4.49 (t, J = 4.7 Hz, 2H),4.32 (t, J = 4.7 Hz, 2H), 3.94 (s, 2H), 2.40 (s, 6H).1-(5-(2-(2-(1H-1,2,4-triazol-1- yl)ethoxy)-4-fluorophenyl)-1H-indazol-3-yl)-N,N- dimethylmethanamine 13

2 A A 9.7 mg, yield over 2 steps: 24% LC-MS rt 8.5 min MH⁺ 408. ¹H NMR(400 MHz, Chloroform-d) δ 7.80 (d, J = 1.2 Hz, 1H), 7.55 (d, J = 8.6 Hz,1H), 7.32 (dd, J = 8.4, 6.8 Hz, 1H), 7.20 (dd, J = 8.7, 1.6 Hz, 1H),6.79 (td, J = 8.3, 2.4 Hz, 1H), 6.67 (dd, J = 10.7, 2.4 Hz, 1H), 6.41(s, 1H), 4.16 (t, J = 5.6 Hz, 2H), 4.07 (t, J = 5.0 Hz, 2H), 3.93 (s,2H), 2.40 (s, 6H), 2.11 (s, 3H), 2.03 (s, 3H).1-(5-(2-(2-(2,4-dimethyl-1H- imidazol-1-yl)ethoxy)-4-fluorophenyl)-1H-indazol-3-yl)- N,N-dimethylmethanamine 14

3 A A 5.4 mg, yield over 2 steps: 15% LC-MS rt 9.4 min MH⁺ 359 ¹H NMR(400 MHz, Chloroform-d) δ 8.76 (d, J = 2.2 Hz, 1H), 8.63 (dd, J = 5.0,1.6 Hz, 1H), 8.05 (d, J = 1.7 Hz, 1H), 7.85 (dt, J = 7.8,1.9 Hz, 1H),7.64 (dd, J = 8.7,1.8 Hz, 1H), 7.53 (d, J = 8.8 Hz, 1H), 7.46-7.34 (m,2H), 7.31-7.29 (m, 1H), 7.28 (s, 1H), 7.01-6.95 (m, 1H), 5.19 (s, 2H),3.91 (s, 2H), 2.38 (s, 6H). N,N-dimethyl-1-(5-(3-(pyridin-3-ylmethoxy)phenyl)-1H- indazol-3-yl)methanamine 15

3 A A 6.1 mg, yield over 2 steps: 17% LC-MS rt 8.8 min MH⁺ 359. ¹H NMR(400 MHz, Chloroform-d) δ 8.69- 8.63 (m, 2H), 8.05 (d, J = 1.5 Hz, 1H),7.64 (dd, J = 8.7, 1.6 Hz, 1H), 7.53 (d, J = 8.7 Hz, 1H), 7.46-7.41 (m,2H), 7.40 (d, 1H), 7.32-7.27 (m, 2H), 6.95 (dd, J = 8.2, 2.5 Hz, 1H),5.21 (s, 2H), 3.95 (s, 2H), 2.40 (s, 6H). N,N-dimethyl-1-(5-(3-(pyridin-4-ylmethoxy)phenyl)-1H- indazol-3-yl)methanamine 16

3 A A 6.1 mg, yield over 2 steps: 17% LC-MS rt 7.7 min MH⁺ 362 ¹H NMR(400 MHz, Chloroform-d) δ 8.02 (d, J = 1.4 Hz, 1H), 7.68 (s, 1H), 7.60(dd, J = 8.6,1.7 Hz, 1H), 7.50 (d, J = 8.7 Hz, 1H), 7.37 (t, J = 8.0 Hz,1H), 7.27 (td, 1H), 7.14 (t, J = 2.1 Hz, 1H), 7.13-7.10 (m, 2H), 6.86(dd, J = 8.1, 2.4 Hz, 1H), 4.40 (t, 2H), 4.33 (t, 2H), 3.94 (s, 2H),2.39 (s, 6H). 1-(5-(2-(3-(1H-imidazol-1- yl)ethoxy)phenyl)-1H-indazol-3-yl)-N,N-dimethylmethanamine 17

6 A 13.5 mg, 31% LC-MS rt 11.6 min MH⁺ 436 ¹H NMR (400 MHz,Chloroform-d) δ 7.88 (d, J = 1.8 Hz, 1H), 7.48 (dd, J = 8.7, 1.5 Hz,1H), 7.35 (d, J = 8.7 Hz, 1H), 7.33- 7.26 (m, 1H), 6.73 (td, J = 8.3,2.5 Hz, 1H), 6.67 (dd, J = 10.8, 2.4 Hz, 1H), 4.08 (s, 3H), 3.93 (t, J =7.2 Hz, 2H), 3.83 (s, 2H), 3.63 (s, 3H), 2.75 (t, J = 7.3 Hz, 2H), 2.33(s, 6H), 2.08 (s, 3H), 1.92 (s, 3H). 1-(5-(4-fluoro-2-(2-(1,3,5-trimethyl-1H-pyrazol-4- yl)ethoxy)phenyl)-1-methyl-1H-indazol-3-yl)-N,N- dimethylmethanamine 18

6 A 40.6 mg, 91% LC-MS rt 11.8 min MH⁺ 422 ¹H NMR (400 MHz, Methanol-d4)δ 7.77 (d, J = 1.4 Hz, 1H), 7.45 (d, J = 8.9 Hz, 1H), 7.40 (dd, J = 8.8,1.5 Hz, 1H), 7.29 (dd, J = 8.5, 6.8 Hz, 1H), 6.83 (dd, J = 11.2, 2.5 Hz,1H), 6.73 (td, J = 8.3, 2.5 Hz, 1H), 4.07 (s, 3H), 4.07 (s, 3H), 4.01(t, J = 6.4 Hz, 2H), 3.55 (s, 2H), 2.71 (t, J = 6.5 Hz, 2H), 2.44 (s,3H), 1.91 (s, 3H), 1.86 (s, 3H). 1-(5-(4-fluoro-2-(2-(1,3,5-trimethyl-1H-pyrazol-4- yl)ethoxy)phenyl)-1-methyl- 1H-indazol-3-yl)-N-methylmethanamine 19

5 General method for alkylation using alkyltosylates 19.9 mg, 56% LC-MSrt 10.4 min MH⁺ 395 ¹H NMR (400 MHz, Chloroform-d) δ 7.93 (s, 1H),7.85-7.77 (m, 2H), 7.39 (d, J = 8.7 Hz, 1H), 7.32 (dd, J = 8.4, 6.8 Hz,1H), 7.23 (dd, J = 8.7, 1.6 Hz, 1H), 6.79 (td, J = 8.1, 2.4 Hz, 1H),6.66 (dd, J = 10.6, 2.4 Hz, 1H), 4.48 (t, J = 4.9 Hz, 2H), 4.30 (t, J =4.8 Hz, 2H), 4.10 (s, 3H), 3.84 (s, 2H), 2.33 (s, 6H).1-(5-(2-(2-(1H-1,2,4-triazol-1- yl)ethoxy)-4-fluorophenyl)-1-methyl-1H-indazol-3-yl)-N,N- dimethylmethanamine 20

4 B 90 mg, 38% LC-MS rt 7.05 min (prep) MH⁺ 436 ¹H NMR (400 MHz,Methanol-d4) δ 8.54 (s, 1H), 7.84-7.77 (m, 1H), 7.53 (d, J = 8.7 Hz,1H), 7.44 (dd, J = 8.8, 1.6 Hz, 1H), 7.30 (dd, J = 8.3, 6.8 Hz, 1H),6.86 (dd, J = 11.2, 2.5 Hz, 1H), 6.76 (td, J = 8.3, 2.5 Hz, 1H), 4.25(s, 2H), 4.13 (s, 3H), 4.03 (t, J = 6.5 Hz, 2H), 3.57 (s, 3H), 2.73 (t,J = 6.4 Hz, 2H), 2.62 (s, 6H), 1.90 (s, 3H), 1.89 (s, 3H).1-(5-(4-fluoro-2-(2-(1,3,5- trimethyl-1H-pyrazol-4-yl)ethoxy)phenyl)-1-methyl- 1H-indazol-3-yl)-N,N- dimethylmethanamineHCl salt 21

5 A 11.7 mg, 44% LC-MS rt 6.7 min (20-98%) MH⁺ 394 ¹H NMR (400 MHz,Methanol-d4) δ 8.35 (s, 2H), 7.71 (d, J = 1.0 Hz, 1H), 7.66 (d, J = 8.6Hz, 1H), 7.42 (dd, J = 8.7, 1.5 Hz, 1H), 7.34-7.27 (m, 2H), 7.08 (s,1H), 6.97 (s, 1H), 6.90 (dd, J = 11.0, 2.4 Hz, 1H), 6.81 (td, J = 8.3,2.2 Hz, 1H), 4.66 (s, 2H), 4.35 (t, J = 4.7 Hz, 2H), 4.30-4.23 (m, 2H),4.20 (s, 3H), 2.99 (s, 6H). 1-(5-(2-(2-(1H-imidazol-1-yl)ethoxy)-4-fluorophenyl)-1- methyl-1H-indazol-3-yl)-N,N-dimethylmethanamine 22

5 A 4.5 mg, 15% LC-MS rt 11.1 min (20-98%) MH⁺ 439 ¹H NMR (400 MHz,Methanol-d4) δ 8.93 (s, 1H), 8.24 (s, 1H), 7.97 (d, J = 8.8 Hz, 1H),7.86 (dd, J = 8.8, 1.6 Hz, 1H), 7.77 (dd, J = 8.5, 6.7 Hz, 1H), 7.33(dd, J = 11.2, 2.5 Hz, 1H), 7.22 (td, J = 8.3, 2.5 Hz, 1H), 4.87 (s,2H), 4.66-4.53 (m, 5H), 3.51 (t, J = 5.8 Hz, 2H), 3.19 (s, 6H), 2.89 (s,3H), 2.44 (s, 3H). 1-(5-(2-(2-(2,4-dimethylthiazol-5-yl)ethoxy)-4-fluorophenyl)-1- methyl-1H-indazol-3-yl)-N,N-dimethylmethanamine 23

5 A 2.8 mg, 44% LC-MS rt 10.3 min (20-98%) MH⁺ 422 ¹H NMR (400 MHz,Methanol- d4) δ 8.50 (s, 1H), 7.97 (d, J = 1.4 Hz, 1H), 7.70 (dd, J =8.8,1.5 Hz, 1H), 7.63 (d, J = 8.6 Hz, 1H), 7.57 (d, J = 8.7 Hz, 1H),7.45 (dd, J = 8.8, 1.6 Hz, 1H), 7.32 (td, 9.1, 8.7, 6.8 Hz, 1H), 6.90(dd, J = 11.2, 2.5 Hz, 1H), 6.77 (td, J = 8.3, 2.5 Hz, 1H), 6.71-6.65(m, 1H), 4.56 (s, 1H), 4.51 (s, 1H), 4.17 (s, 2H), 4.16 (s, 2H), 4.08(t, J = 6.4 Hz, 2H), 2.85 (s, 3H), 2.83 (s, 3H), 2.76 (t, J = 6.4 Hz,2H), 1.91 (s, 6H). 1-(5-(2-(2-(3,5-dimethyl-1H- pyrazol-4-yl)ethoxy)-4-fluorophenyl)-1-methyl-1H- indazol-3-yl)-N,N- dimethylmethanamine 24

5 A 14.5 mg, 57% LC-MS rt 11.6 min (20-98%) MH⁺ 424 (400 MHz,Methanol-d4) δ 8.67 (s, 1H), 8.54 (s, 1H), 7.81 (d, J = 1.2 Hz, 1H),7.52 (d, J = 8.7 Hz, 1H), 7.41 (dd, J = 8.9,1.4 Hz, 1H), 7.34 (dd, J =8.4, 6.7 Hz, 1H), 6.91 (dd, J = 11.1, 2.5 Hz, 1H), 6.80 (td, J = 8.3,2.4 Hz, 1H), 4.40 (s, 2H), 4.22 (t, J = 5.8 Hz, 2H), 4.15 (s, 3H), 3.19(t, J = 5.8 Hz, 2H), 2.73 (s, 6H), 2.11 (s, 3H).1-(5-(2-(2-(4-methylthiazol-5- yl)ethoxy)-4-fluorophenyl)-1-methyl-1H-indazol-3-yl)-N,N- dimethylmethanamine 25

7 C 22 mg, 55% LC-MS rt 12.6 min (5-98%) MH⁺ 411. ¹H NMR (400 MHz,Chloroform-d) δ 8.69 (s, 1H), 7.67 (d, J = 1.1 Hz, 1H), 7.39 (dd, J =8.9, 1.7 Hz, 1H), 7.34- 7.30 (m, 1H), 7.30-7.27 (m, 1H), 6.73 (td, J =8.3, 2.5 Hz, 1H), 6.68 (dd, J = 10.8, 2.4 Hz, 1H), 5.32 (s, 2H), 4.80(q, J = 6.8 Hz, 1H), 4.20- 4.07 (m, 2H), 4.04 (s, 3H), 3.21- 3.06 (m,2H), 2.07 (s, 3H), 1.81 (d, J = 6.8 Hz, 3H). 1-(5-(4-fluoro-2-(2-(4-methylthiazol-5- yl)ethoxy)phenyl)-1-methyl- 1H-indazol-3-yl)ethanamine26

Product from example 25 D 3.1 mg, 26% LC-MS rt 12.8 min (5-98%) MH⁺ 439¹H NMR (400 MHz, Methanol-d4) δ 8.67 (s, 1H), 8.50 (s, 1H), 7.82 (d, J =0.9 Hz, 1H), 7.55 (d, J = 8.7 Hz, 1H), 7.42 (dd, J = 8.8, 1.4 Hz, 1H),7.34 (dd, J = 8.5, 6.7 Hz, 1H), 6.92 (dd, J = 11.1, 2.5 Hz, 1H), 6.81(td, J = 8.3, 2.4 Hz, 1H), 4.23 (t, J = 5.7 Hz, 2H), 4.17 (s, 3H), 3.20(t, J = 5.8 Hz, 2H), 2.80 (s, 6H), 2.11 (s, 3H), 1.84 (d, J = 6.9 Hz,3H). 1-(5-(4-fluoro-2-(2-(4- methylthiazol-5-yl)ethoxy)phenyl)-1-methyl- 1H-indazol-3-yl)-N,N- dimethylethanamine 27

8 D general method for benzamide deprotection 15 mg, 64% LC-MS rt 10.9min (5-98%) MH⁺ 384. ¹H NMR (400 MHz, Methanol-d4) δ 8.66 (s, 1H), 8.46(d, J = 1.5 Hz, 1H), 7.73-7.65 (m, 1H), 7.51-7.44 (m, 3H), 6.99 (dd, J =11.1, 2.4 Hz, 1H), 6.85 (td, J = 8.3, 2.4 Hz, 1H), 4.51 (s, 2H), 4.29(t, J = 5.8 Hz, 2H), 3.26 (t, J = 5.8 Hz, 2H), 2.20 (s, 3H).(6-(4-fluoro-2-(2-(4- methylthiazol-5- yl)ethoxy)phenyl)-[1,2,4]triazolo[4,3-a]pyridin-3- yl)methanamine 28

8 D general method for benzamide deprotection 20 mg, 86% LC-MS rt 11.0min (5-98%) MH⁺ 395 ¹H NMR (400 MHz, Chloroform-d) δ 8.32 (d, J = 1.4Hz, 1H), 7.73 (d, J = 9.8 Hz, 1H), 7.37 (dd, J = 9.5, 1.6 Hz, 1H), 7.31(dd, J = 8.4, 6.5 Hz, 1H), 6.78 (td, J = 8.1, 2.4 Hz, 1H), 6.72 (dd, J =10.8, 2.5 Hz, 1H), 4.45 (s, 2H), 4.00 (t, J = 7.2 Hz, 2H), 3.66 (s, 3H),2.79 (t, J = 7.2 Hz, 2H), 2.11 (s, 3H), 1.99 (s, 3H), 1.81 (s, 2H).(6-(4-fluoro-2-(2-(1,3,5- trimethyl-1H-pyrazol-4- yl)ethoxy)phenyl)-[1,2,4]triazolo[4,3-a]pyridin-3- yl)methanamine 29

9 E 24 mg, 40% LC-MS rt 12.2 min (5-98%) MH⁺ 436 ¹H NMR (400 MHz, CDCl₃)δ 8.38 (s, 1H), 7.87 (s, 1H), 7.64-7.47 (m, 2H), 7.15-6.97 (m, 3H), 4.64(s, 2H), 4.17 (s, 3H), 3.97 (t, J = 6.5 Hz, 2H), 3.55 (s, 3H), 2.91 (s,6H), 2.69 (t, J = 6.5 Hz, 2H), 1.92 (s, 3H), 1.87 (s, 3H).1-(5-(5-fluoro-2-(2-(1,3,5- trimethyl-1H-pyrazol-4-yl)ethoxy)phenyl)-1-methyl- 1H-indazol-3-yl)-N,N- dimethylmethanamine 30

10 E 40 mg, 33% LC-MS rt 12.3 min (5-98%) MH⁺ 436 ¹H NMR (400 MHz, MeOD)δ 8.39 (s, 1H), 7.89 (d, J = 4.0 Hz, 1H), 7.62- 7.51 (m, 2H), 7.19 (h, J= 5.1 Hz, 3H), 4.64 (s, 2H), 4.20 (s, 3H), 3.76 (t, J = 6.9 Hz, 2H),3.49 (s, 3H), 2.93 (s, 6H), 2.59 (t, J = 6.8 Hz, 2H), 1.90 (s, 3H), 1.88(s,3H). 1-(5-(3-fluoro-2-(2-(1,3,5- trimethyl-1H-pyrazol-4-yl)ethoxy)phenyl)-1-methyl- 1H-indazol-3-yl)-N,N- dimethylmethanamine 36

2 E B 23.8 mg, 43% LC-MS rt 11.6 min MH⁺ 411. ¹H NMR (400 MHz, MeOD)8.66 (s, 1H), 8.50 (s, 1H), 7.85-7.80 (m, 1H), 7.53 (d, J = 8.7 Hz, 1H),7.39 (dd, J = 8.7, 1.4 Hz, 1H), 7.34 (dd, J = 8.5, 6.7 Hz, 1H), 6.90(dd, J = 11.2, 2.5 Hz, 1H), 6.79 (td, J = 8.4, 2.5 Hz, 1H), 4.61 (s,2H), 4.21 (t, J = 5.8 Hz, 2H), 3.18 (t, J = 5.7 Hz, 2H), 2.87 (s, 6H),2.09 (s, 3H). 1-(5-(4-fluoro-2-(2-(4- methylthiazol-5-yl)ethoxy)phenyl)-1H-indazol- 3-yl)-N,N-dimethylmethanamine 37

11 B 40 mg; 28% LC-MSrt 10.5 min MH⁺ 423 ¹H NMR (400 MHz, Methanol-d4)8.54 (d, J = 1.4 Hz, 1H), 8.20 (s, 1H), 7.72 (d, J = 9.4 Hz, 1H), 7.52(dd, J = 9.3, 1.4 Hz, 1H), 7.43 (dd, 7 = 8.5, 6.6 Hz, 1H), 6.94 (dd, J =10.9, 2.4 Hz, 1H), 6.82 (td, J = 8.3, 2.4 Hz, 1H), 4.30 (s, 2H), 4.12(t, J = 6.6 Hz, 2H), 3.60 (s, 3H), 2.81 (t, J = 6.6 Hz, 2H), 2.51 (s,6H), 1.99 (s, 3H), 1.98 (s, 3H). 1-(6-(4-fluoro-2-(2-(1,3,5-trimethyl-1H-pyrazol-4- yl)ethoxy)phenyl)-[1,2,4]triazolo[4,3-a]pyriclin-3- yl)-N,N-dimethylmethanamine 38

12 B A 46 mg, 56% LC-MS rt 10.3 min MH⁺ 398. ¹H NMR (400 MHz,Methanol-d4) δ 8.66 (s, 1H), 8.50 (d, J = 1.4 Hz, 1H), 8.41 (s, 1H),7.72 (d, J = 9.5 Hz, 1H), 7.51 (dd, J = 9.5, 1.5 Hz, 1H), 7.46 (dd, J =8.5, 6.6 Hz, 1H), 7.00 (dd, J = 11.1, 2.5 Hz, 1H), 6.86 (td, J = 8.3,2.4 Hz, 1H), 4.63 (s, 2H), 4.30 (t, J = 5.9 Hz, 2H), 3.26 (t, J = 5.8Hz, 2H), 2.73 (s, 3H), 2.21 (s, 3H). 1-(6-(4-fluoro-2-(2-(4-methylthiazol-5- yl)ethoxy)phenyl)- [1,2,4]triazolo[4,3-a]pyridin-3-yl)-N-methylmethanamine 39

13 B A 53mg, 61% LC-MS rt 10.6 min MH⁺ 409. ¹H NMR (400 MHz,Methanol-d4) 8.51-8.45 (m, 1H), 8.33 (s, 1H), 7.74 (d, J = 9.7 Hz, 1H),7.54 (dd, J = 9.3, 1.5 Hz, 1H), 7.44 (dd, J = 8.5, 6.5 Hz, 1H), 6.97(dd, J = 11.2, 2.4 Hz, 1H), 6.84 (td, J = 8.3, 2.5 Hz, 1H), 4.69 (s,2H), 4.13 (t, J = 6.5 Hz, 2H), 3.60 (s, 3H), 1.95 (s, 3H).1-(6-(4-fluoro-2-(2-(1,3,5- trimethyl-1H-pyrazol-4- yl)ethoxy)phenyl)-[1,2,4]triazolo[4,3-a]pyridin-3- yl)-N-methylmethanamine 40

13 B 28 mg; 24% LC-MSrt 11.2 min MH⁺ 428 ¹H NMR (400 MHz, Chloroform-d)δ 8.49 (s, 1H), 8.45-8.39 (m, 1H), 7.72 (d, J = 9.4 Hz, 1H), 7.36-7.26(m, 2H), 7.08 (dd, J = 8.1, 2.0 Hz, 1H), 6.98 (d, J = 2.0 Hz, 1H), 4.19(t, J = 6.3 Hz, 2H), 4.00 (s, 2H), 3.21 (t, J = 6.3 Hz, 2H), 2.31 (s,6H), 2.26 (s, 5H). 1-(6-(4-chloro-2-(2-(4- methylthiazol-5-yl)ethoxy(phenyl)- [1,2,4]triazolo[4,3-a]pyridin-3-yl)-N,N-dimethylmethanamine 41

4 B 42 mg; 31% LC-MSrt 10.5 min MH⁺ 423 ¹H NMR (400 MHz, Methanol-d4) δ8.58 - 8.51 (m, 1H), 8.26 (s, 1H), 7.72 (d, J = 9.3 Hz, 1H), 7.52 (dd, J= 9.8, 1.8 Hz, 1H), 7.40 (d, J = 8.2 Hz, 1H), 7.16 (d, J = 2.0 Hz, 1H),7.09 (dd, J = 8.0, 1.9 Hz, 1H), 4.15 (s, 2H), 4.12 (t, J = 6.7 Hz, 2H),3.60 (s, 3H), 2.81 (t, J = 6.5 Hz, 2H), 2.39 (s, 6H), 1.98 (s, 6H).1-(6-(4-chloro-2-(2-(1,3,5- trimethyl-1H-pyrazol-4- yl)ethoxy)phenyl)-[1,2,4]triazolo[4,3-a]pyridin-3- yl)-N,N-dimethylmethanamine 42

11 B 42 mg; 25% LC-MSrt 12.0 min, MH⁺ 465. ¹H NMR (400 MHz, Methanol-d4)δ 8.51 (d, J = 6.3 Hz, 1H), 8.26 (s, 1H), 7.79-7.65 (m, 1H), 7.53 (dd, J= 9.6, 1.6 Hz, 1H), 7.44 (dd, J = 8.5, 6.6 Hz, 1H), 6.94 (ddd, J = 11.1,5.2, 2.5 Hz, 1H), 6.83 (td, J = 8.3, 2.5 Hz, 1H), 4.22-4.03 (m, 4H),3.63 (s, 3H), 2.22 (d, J = 7.4 Hz, 2H), 2.02 (s, 3H), 1.90-1.71 (m, 1H),0.88-0.72 (m, 6H). 1-(6-(4-fluor-2-(2-(3-isobutyl-1,5-dimethyl-1H-pyrazol-4- yl)ethoxy)phenyl)-[1,2,4]triazolo[4,3-a]pyridin-3- yl)-N,N-dimethylmethanamine 43

11 B 51 mg; 30% L.C-MS rt 12.2 min, MH⁺ 465. ¹H NMR (400 MHz,Methanol-d4) 8.53 (d, J = 1.5 Hz, 1H), 8.21 (s, 1H), 7.72 (d, J = 9.5Hz, 1H), 7.51 (dd, J = 9.6, 1.5 Hz, 1H), 7.43 (dd, J = 8.5, 6.6 Hz, 1H),6.98-6.90 (m, 1H), 6.82 (td, J = 8.3, 2.4 Hz, 1H), 4.28 (s, 2H), 4.14(t, J = 6.6 Hz, 2H), 3.63 (s, 3H), 2.82 (t, J = 6.6 Hz, 2H), 2.49 (s,6H), 2.26 (d, J = 7.5 Hz, 2H), 2.02 (s, 3H), 1.81-1.67 (m, 1H), 0.82 (d,J = 6.5 Hz, 6H). 1-(6-(4-fluoro-2-(2-(5-isobutyl-1,3-dimethyl-1H-pyrazol-4- yl)ethoxy)phenyl)-[1,2,4]triazolo[4,3-a]pyridin-3- yl)-N,N-dimethylmethanamine 45

15 B B 71 mg, ~100% LC-MS rt 10.8 min MH⁺ 421. ¹H NMR (400 MHz, DMSO-d6)δ 8.40 (s, 1H), 7.78 (d, 1H), 7.56 (d, 1H), 7.40 (dd, 1H), 7.02 (dd,1H). 6.88 (td, 1H), 4.68 (m, 1H), 4.43 (m, 4H), 4.03 (t, 2H), 3.58 (s,3H), 2.71 (t, 2H), 1.97 (s, 3H), 1.90 (s, 3H).4-(2-(2-(3-(azetidin-3-yl)- [1,2,4]triazolo(4,3-a]pyridin-6-yl]-5-fluorophenoxylethyl)- 1,3,5-trimethyl-1H-pyrazole 48

13 B B 15 mg, ~100% LC-MS rt 10.3 min MH⁺ 466. ¹H NMR (400 MHz, DMSO-d6)δ 9.37 (br.s, 2H), 8.71 (s, 1H), 7.78 (d, 1H), 7.52 (d, 1H), 7.49 (dd,1H), 7.11 (dd, 1H), 6.91(td, 1H), 4.78 (s, 2H), 4.09 (t, 2H), 3.65 (s,3H), 3.04 (s, 3H), 2.88 (s, 3H), 2.81 (t, 2H), 2,67 (t, 3H), 1.99 (s,3H). 4-[2-(S-fluoro-2-(3- (methylamino)methyl]-[1,2,4]triazolo[4,3-a]pyridin-6- yl]phenoxy)eyhyl]-N,N,1,5-tetramethyl-1H-pyrazole-3- carboxamide 49

17 E 170 mg, 99% LC-MS rt 12.2 min (5-98%) MH⁺ 454 ¹H NMR (400 MHz,Chloroform-d) δ 7.85 (s, 1H), 7.45 (d, J = 8.5 Hz, 1H), 7.31 (d, J = 8.8Hz, 1H), 7.07 (ddd, J = 8.3, 5.7, 2.1 Hz, 1H), 6.91 (q, J = 8.6 Hz, 1H),4.04 (s, 3H), 3.81 (s, 3H), 3.70 (t, J = 7.5 Hz, 2H), 3.53 (s, 3H), 2.55(t. J = 7.6 Hz, 2H), 2.29 (s, 6H), 1.89 (s, 3H), 1.85 (s, 3H).1-(5-(3,4-difluoro-2-(2-(1,3,5- trimethyl-1H-pyrazol-4-yl)ethoxy)phenyl)-1-methyl- 1H-indazol-3-yl)-N,N- dimethylmethanamine 53

24 B B 44 mg, 99% hplc rt 3.9 min LC-MS MH⁺ 408; ¹H NMR (400 MHz,DMSO-d6) δ 9.70 (s, 1H), 9.18 (s, 1H), 8.40 (s, 1H), 8.07 (d, 1H), 7.99(d, 1H), 7.72 (td, 1H), 7.14 (dd, 1H), 6.99 (td, 1H), 4.73 (s, 2H), 4.07(t, 2H), 3.63 (s, 3H), 2.74 (t, 2H), 2.67 (s, 3H), 2.03 (s, 3H), 1.97(s, 3H). [(6-(4-fluoro-2-[2-(1,3,5- trimethyl-1H-pyrazol-4-yl)ethoxy)phenyl)imidazo[1,2- a]pyridio-3- yl)methyl(methyl)amine 54

12 B 25 mg, 94% hplc rt 4.7 min LC-MS MH⁺ 445; ¹H NMR (400 MHz, DMSO-d6)δ 8.96 (s, 1H), 8.24 (s, 1H), 7.95 (d, 1H), 7.89 (d, 1H), 7.51 (dd, 1H),7.05 (d, 1H), 6.93 (d, 1H), 4.66 (s, 2H), 3.97 (t, 2H), 3.58 (s, 3H),2.70 (t, 2H), 2.63 (s, 3H), 1.94 (s, 3H), 1.84 (s, 3H).([6-(2-(2-[1-(difluoromethyl)- 3,5-dimethyl-1H-pyrazol-4-yl)ethoxy)-4-fluorophenyl)- [1,2,4]triazolo[4,3-a]pyridin-3-yl]lmethyl)(methyl)amine 55

12 B B 80 mg, 97% LC-MS MH⁺ 463; ¹H NMR (400 MHz, DMSO-d₆) δ 9.30 (s,2H), 8.71 (s, 1H), 7.79 (d, 1H), 7.49 (td, 1H),7.47 (d, 1H), 7.12 (dd,1H), 6.96 (td, 1H), 4.81 (t, 2H), 4.10 (t, 2H), 3.72 (s, 3H), 2.87 (t,2H), 2.71 (t, 2H), 2.01 (s, 3H) ([6-(2-(2-[1,5-dimethyl-3-(trifluoromethyl)-1H-pyrazol-4- yl]ethoxy)-4-fluorophenyl)-[1,2,4]triazolo[4,3-a)pyridin-3- yl]methyl)(methyl)amine 66

18 B C 10 mg, 97% LC-MS MH⁺ 478; ¹H NMR (400 MHz, DMSO-d₆) δ 9.05 (br.s1H), 8.97 (br.s, 1H), 8.44 (s, 1H), 7.76 (d, 1H), 7.47 (d, 1H), 7.40(td, 1H), 7.11 (dd, 1H), 6.92 (td, 1H), 4.72 (m, 2H), 4.45 (m, 4H), 4.10(t, 2H), 3.67 (s, 3H), 3.06 (s, 3H), 2.88 (5, 3H), 2.84 (t, 2H), 2.01(s, 3H). 4-(2-(2-[3-(azetidin-3-yl)- [1,2,4]triazolo[4,3-a]pyridin-6-yl]-5-fluorophenoxy)ethyl)- N,N,1,5-tetramethyl-1H-pyrazole-3-carboxamide 67

16 B B 4 mg, 60% LC-MS MH⁺ 480; ¹H NMR (400 MHz, CD₃OD) δ 8.88 (s, 1H),8.23 (d, 1H), 8.04 (d, 1H), 7.54 (td, 1H), 7.05 (dd, 1H), 6.91 (td, 1H),4.20 (t, 2H), 3.77 (s, 3H), 3.75-3.70 (m, 4H), 3.07 (s, 3H), 2.97-2.90(m, 5H), 2.87 (s, 3H), 2.19 (s, 3H). 4-[2-(5-fluoro-2-{3-2(methylamino)ethyl]- [1,2,4triazolo[4,3-a]pyridin-6-yl)phenoxy)ethyl]-N,N,1,5- tetramethyl-1H-pyrazole-3- carboxamide 69

22 B B 10 mg, 83% LC-MS MH⁺ 406; ¹H NMR (400 MHz, DMSO-d₆) δ 8.92 (s,1H), 8.14 (s, 1H), 8.10 (br.s, 2H), 8.00 (dd, 1H), 7.55 (td, 1H), 7.15(dd, 1H), 6.97 (td, 18), 4.05 (t, 2H), 3.59 (S, 3H), 3.42 (t, 2H), 3.20(m, 2H), 2.71 (t, 2H), 2.02 (s, 3H), 1.92 (s, 3H).2-(6-(4-fluoro-2-[2-(1,3,5- trimethyl-1H-pyrazol-4-yl)ethoxy]phenyl)imidazo[1,2- a]pyridin-3-yl)ethan-1-amine

Example 31

(5-(4-fluoro-2-(2-(1,3,5-trimethyl-1H-pyrazol-4-yl)ethoxy)phenyl)-1-methyl-1H-indazol-3-yl)methanamine

Intermediate 6 (240 mg; 0.59 mmol) in ethanol (10 mL) was treated withhydroxylamine hydrochloride (74 mg; 1.06 mmol) and sodium acetate (97mg; 1.18 mmol) and the reaction was stirred for 15 hours at roomtemperature. Water (50 mL) was added and the resulting solid oximeisolated by filtration (197 mg colourless solid, MH*422). mp 230-233° C.The solid (100 mg) in methanol (6 mL) was treated with zinc dust (155mg, 2.4 mmol) and ammonium formate (150 mg, 2.4 mmol). The suspensionwas heated under reflux for 4 hours before being cooled to roomtemperature and filtered through celite. Methanol was removed underreduced pressure and the residue purified by LC-MS by gradient elutionwith methanol/water/formic acid (50:50:0.1 to 98:2:0.1). Fractionscontaining the desired product were combined and evaporated underreduced pressure to give the title compound as a colourless solidformate salt (30 mg, 28%). LC-MS rt 11.9 min (5-98%) MH⁺ 408. ¹H NMR(400 MHz, MeOD) δ 8.56 (s, 1H), 7.70 (s, 1H), 7.54 (d, J=8.8 Hz, 1H),7.45 (dd, J=8.7, 1.4 Hz, 1H), 7.30 (dd, J=8.4, 6.7 Hz, 1H), 6.89 (dd,J=11.1, 2.4 Hz, 1H), 6.77 (td, J=8.3, 2.4 Hz, 1H), 4.45 (s, 2H), 4.14(s, 3H), 4.06 (t, J=6.3 Hz, 2H), 3.56 (s, 3H), 2.74 (t, J=6.3 Hz, 2H),1.92 (s, 3H), 1.85 (s, 3H).

Example 32

1-(5-(5-fluoro-2-(2-(1,3,5-trimethyl-1H-pyrazol-4-yl)ethoxy)phenyl)-1-methyl-1H-indazol-3-yl)methanamine

Intermediate 9 (50 mg; 0.123 mmol) in ethanol (3 mL) was treated withhydroxylamine hydrochloride (15 mg; 0.22 mmol) and sodium acetate (20mg; 0.25 mmol) and the reaction was stirred for 15 hours at roomtemperature. Water (20 mL) was added and the resulting solid oximeisolated by filtration (31 mg colourless solid, MH*422). The solid (31mg) in methanol (2 mL) was treated with zinc dust (48 mg, 0.70 mmol) andammonium formate (46 mg, 0.70 mmol). The suspension was heated underreflux for 3 hours before being cooled to room temperature and filteredthrough celite. Methanol was removed under reduced pressure and theresidue purified by LC-MS by gradient elution with methanol/water/formicacid (50:50:0.1 to 98:2:0.1). Fractions containing the desired productwere combined and evaporated under reduced pressure to give the titlecompound as a colourless solid formate salt (7.7 mg, 23%). LC-MS rt 2.91min (50-98%) MH⁺ 408. ¹H NMR (400 MHz, MeOD) δ 8.54 (s, 1H), 7.76 (s,1H), 7.60-7.48 (m, 2H), 7.12-7.00 (m, 3H), 4.49 (s, 2H), 4.15 (s, 3H),3.99 (t, J=6.4 Hz, 2H), 3.54 (s, 3H), 2.71 (t, J=6.4 Hz, 2H), 1.92 (s,3H), 1.87 (s, 3H).

Example 33

1-(5-(3-fluoro-2-(2-(1,3,5-trimethyl-1H-pyrazol-4-yl)ethoxy)phenyl)-1-methyl-1H-indazol-3-yl)methanamine

Intermediate 10 (100 mg; 0.25 mmol) in ethanol (6 mL) was treated withhydroxylamine hydrochloride (31 mg; 0.44 mmol) and sodium acetate (40mg; 0.49 mmol) and the reaction was stirred for 15 hours at roomtemperature. Water (20 mL) was added and the resulting solidoxime-isolated by filtration (68 mg colourless solid, MH⁺ 422). Thesolid (68 mg) in methanol (4 mL) was treated with zinc dust (105 mg,1.61 mmol) and ammonium formate (101 mg, 0.61 mmol). The suspension washeated under reflux for 3 hours before being cooled to room temperatureand filtered through celite. Methanol was removed under reduced pressureand the residue purified by LC-MS by gradient elution withmethanol/water/formic acid (50:50:0.1 to 98:2:0.1). Fractions containingthe desired product were combined and evaporated under reduced pressureto give the title compound as a colourless solid formate salt (10.1 mg,14%). LC-MS rt 3.11 min (50-98%) MH⁺ 408; ¹H NMR (400 MHz, MeOD) δ 8.38(s, 1H), 7.78-7.74 (m, 1H), 7.57-7.50 (m, 2H), 7.20-7.13 (m, 3H), 4.50(s, 2H), 4.16 (s, 3H), 3.76 (t, J=6.6 Hz, 2H), 3.43 (s, 3H), 2.59 (t,J=6.6 Hz, 2H), 1.92 (s, 3H), 1.85 (s, 3H).

Example 34

1-(5-(5-fluoro-2-(2-(1,3,5-trimethyl-1H-pyrazol-4-yl)ethoxy)phenyl)-1-methyl-1H-indazol-3-yl)-N-methylmethanamine

Intermediate 9 (40 mg; 0.1 mmol) in THF (5 mL) was treated with asolution of methylamine in ethanol (2M, 2 ml, 40 mmol) then stirred atroom temperature overnight. The mixture was evaporated under reducedpressure and the residue redissolved in ethanol (5 ml) then treated withsodium borohydride (19 mg; 0.49 mmol) and stirred at room temperaturefor 4 h. Excess borohydride was quenched by addition of hydrochloricacid (1M, 2 ml) and the mixture was evaporated under reduced pressure.The residue was partitioned between ethyl acetate and saturated sodiumcarbonate solution (10 ml each). The organic phase was dried (MgSO₄) andevaporated under reduced pressure. The crude product was purified byLC-MS by gradient elution with methanol/water/formic acid (20:80:0.1 to98:2:0.1). Fractions containing the desired product were combined andevaporated under reduced pressure to give the title compound as acolourless solid formate salt (5.6 mg, 12%). LC-MS rt 11.9 min (5-98%)MH⁺ 422; ¹H NMR (400 MHz, MeOD) δ 8.38 (s, 1H), 7.78-7.74 (m, 1H),7.57-7.50 (m, 2H), 7.20-7.13 (m, 3H), 4.50 (s, 2H), 4.16 (s, 3H), 3.76(t, J=6.6 Hz, 2H), 3.43 (s, 3H), 2.59 (t, J=6.6 Hz, 2H), 1.92 (s, 3H),1.85 (s, 3H).

Example 35

1-(5-(3-fluoro-2-(2-(1,3,5-trimethyl-1H-pyrazol-4-yl)ethoxy)phenyl)-1-methyl-1H-indazol-3-yl)-N-methylmethanamine

Intermediate 10 (40 mg; 0.1 mmol) in THF (5 mL) was treated with asolution of methylamine in ethanol (2M, 2 ml, 40 mmol) then stirred atroom temperature overnight. The mixture was evaporated under reducedpressure and the residue redissolved in ethanol (5 ml) then treated withsodium borohydride (19 mg; 0.49 mmol) and stirred at room temperaturefor 4 h. Excess borohydride was quenched by addition of hydrochloricacid (1M, 2 ml) and the mixture was evaporated under reduced pressure.The residue was partitioned between ethyl acetate and saturated sodiumcarbonate solution (10 ml each). The organic phase was dried (MgSO₄) andevaporated under reduced pressure. The crude product was purified byLC-MS by gradient elution with methanol/water/formic acid (20:80:0.1 to98:2:0.1). Fractions containing the desired product were combined andevaporated under reduced pressure to give the title compound as acolourless solid formate salt (6.6 mg, 14%). LC-MS rt 12.1 min (5-98%)MH⁺ 422; ¹H NMR (400 MHz, MeOD) δ 7.81 (s, 1H), 7.63-7.46 (m, 2H),7.14-6.99 (m, 3H), 4.59 (s, 2H), 4.17 (s, 3H), 4.00 (t, J=6.5 Hz, 2H),3.56 (s, 3H), 2.85 (s, 3H), 2.72 (t, J=6.4 Hz, 2H), 1.93 (s, 3H), 1.89(s, 3H).

Example 44

4-(2-{5-fluoro-2-[3-(pyrrolidin-2-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yl]phenoxy}ethyl)-1,3,5-trimethyl-1H-pyrazoleStep 1

According to the general method for mesyl transfer (Method B),intermediate 14 (205 mg, 0.43 mmol was reacted with2-(1,3,5-trimethyl-1H-pyrazol-4-yl)ethanol (120 mg, 0.78 mmol) andcesium carbonate (190 mg, 0.58 mmol) in DMF (5.0 ml). Purification byhplc by elution with acetonitrile/water/ammonium carbonate followed byfreeze-drying of the appropriate fractions provided tert-butyl2-(6-{4-fluoro-2-[2-(1,3,5-trimethyl-1H-pyrazol-4-yl)ethoxy]phenyl}-[1,2,4]triazolo[4,3-a]pyridin-3-yl)pyrrolidine-1-carboxylateas a solid (72 mg; 31%). ¹H NMR (400 MHz, DMSO-d6) as a mixture ofrotamers 6 8.51 (d, 1H), 7.71 (m, 1H), 7.39 (m, 2H), 7.07 (d, 1H), 6.91(dd, 1H), 5.44 (m, 1H), 4.03 (t, 2H), 3.54-3.48 (m, 5H), 2.49 (m, 2H),2.32 (m, 2H), 2.13 (m, 2H), 1.97 (s, 3H), 1.92 (s, 3H), 1.33+0.92 (s,9H).

Step 2

According to the general method for Boc deprotection, the product fromStep 1 (70 mg) was dissolved in dioxane (2 ml) and treated with asolution of HCl in dioxane (4M, 3 ml). The solution was stirred at roomtemperature for 3 hr. The solvent was removed under reduced pressure andthe residue triturated with diethyl ether. The crude product wasdissolved in water and freeze-dried to provide the title compound as ahydrochloride salt (45 mg, 79%) LC-MS rt 10.8 min MH⁺ 435. ¹H NMR (400MHz, DMSO-d6) δ 8.55 (s, 1H), 7.77 (d, 1H), 7.50 (d, 1H), 7.43 (dd, 1H),7.04 (dd, 1H), 6.90 (td, 1H), 5.32 (t, 1H), 4.06 (t, 2H), 3.58 (s, 3H),3.39 (t, 2H), 2.73 (m, 2H), 2.21 (m, 1H), 2.10 (m, 1H), 1.97 (s, 3H),1.90 (s, 3H).

Example 46

[2-(6-{4-fluoro-2-[2-(1,3,5-trimethyl-1H-pyrazol-4-yl)ethoxy]phenyl}-[1,2,4]triazolo[4,3-a]pyridin-3-yl)ethyl](methyl)amineStep 1

According to the general method for mesyl transfer (Method B),intermediate 16 (220 mg, 0.47 mmol was reacted with2-(1,3,5-trimethyl-1H-pyrazol-4-yl)ethanol (132 mg, 0.86 mmol) andcesium carbonate (209 mg, 0.64 mmol) in DMF (5.0 ml). The crude productwas partially purified by column chromatography by elution withdichloromethane/acetone (80:20). Further purification by hplc by elutionwith acetonitrile/water/ammonium carbonate followed by freeze-drying ofthe appropriate fractions provided tert-butylN-[2-(6-{4-fluoro-2-[2-(1,3,5-trimethyl-1H-pyrazol-4-yl)ethoxy]phenyl}-[1,2,4]triazolo[4,3-a]pyridin-3-yl)ethyl]-N-methylcarbamateas a solid (80 mg; 32%). ¹H NMR (400 MHz, DMSO-d6) as a mixture ofrotamers 6 8.51 (d, 1H), 7.71 (m, 1H), 7.39 (m, 2H), 7.07 (d, 1H), 6.91(dd, 1H), 5.44 (m, 1H), 4.03 (t, 2H), 3.54-3.48 (m, 5H), 2.49 (m, 2H),2.32 (m, 2H), 2.13 (m, 2H), 1.97 (s, 3H), 1.92 (s, 3H), 1.33+0.92 (s,9H).

Step 2

According to the general method for Boc deprotection, the product fromStep 1 (80 mg) was dissolved in dioxane (2 ml) and treated with asolution of HCl in dioxane (4M, 3 ml). The solution was stirred at roomtemperature for 3 hr. The solvent was removed under reduced pressure andthe residue triturated with diethyl ether. The crude product wasdissolved in water and freeze-dried to provide the title compound as alight yellow hydrochloride salt (50 mg, 77%) LC-MS rt 10.9 min MH⁺ 423.¹H NMR (400 MHz, DMSO-d6) δ 9.08 (br.s, 2H), 8.75 (s, 1H), 7.90 (d, 1H),7.75 (d, 1H), 7.51 (t, 1H), 7.12 (dd, 1H), 6.96 (td, 1H), 4.08 (t, 2H),3.64 (s, 3H), 3.60 (t, 2H), 3.44 (t, 2H), 2.76 (m, 2H), 2.62 (t, 2H),2.04 (s, 3H), 1.99 (s, 3H).

Example 47

N-methyl[(6-{3-[2-(1,3,5-trimethyl-1H-pyrazol-4-yl)ethoxy]pyridin-2-yl}-[1,2,4]triazolo[4,3-a]pyridin-3-yl)methyl]amineStep 1

A solution of tert-butyl((6-bromo-[1,2,4]triazolo[4,3-a]pyridin-3-yl)methyl)(methyl)carbamate(Intermediate 12, Step 2, 550 mg, 1.61 mmol), bis(pinacolato)diboron(491 mg, 1.9 mmol) and potassium acetate (474 mg, 4.8 mmol) in dioxane(10 ml) was degassed with argon for 15 min, before addition ofdichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium(II)dichloromethane adduct (131 mg, 0.61 mmol). The reaction mixture washeated under reflux overnight under an argon atmosphere, cooled to roomtemperature and filtered through Celite, washing with ethyl acetate. Theorganic phase was dried over Na₂SO₄, concentrated under reduced pressureand the crude product purified by flash column chromatography by elutionwith dichloromethane/methanol (95:5) to give tert-butylN-methyl-N-{[6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-yl]methyl}carbamateas a dark solid contaminated with starting borane.

Step 2

A portion of the crude tert-butylN-methyl-N-{[6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-yl]methyl}carbamate(100 mg, 0.84 mmol) was dissolved in dioxane (10 ml) and treated with2-bromo-3-[2-(1,3,5-trimethyl-1H-pyrazol-4-yl)ethoxy]pyridine (213 mg,1.7 mmol) and a solution of potassium carbonate (173 mg, 1.26 mmol) inwater (2 ml). The mixture was purged with argon for 15 min beforeaddition of dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium(II)dichloromethane adduct (34 mg, 0.04 mmol) and the reaction mixture washeated under reflux overnight under an argon atmosphere. After beingcooled to room temperature, the mixture was diluted with ethyl acetate,washed with saturated sodium bicarbonate solution, water and brine. Theorganic phase was dried over Na₂SO₄, concentrated under reduced pressureand the crude product purified by flash column chromatography by elutionwith dichloromethane/methanol (96:4) to give tert-butylN-methyl-N-[(6-{3-[2-(1,3,5-trimethyl-1H-pyrazol-4-yl)ethoxy]pyridin-2-yl}-[1,2,4]triazolo[4,3-a]pyridin-3-yl)methyl]carbamateas a solid (80 mg, 39%). ¹H NMR (400 MHz, DMSO-d6) δ 9.01 (br.s, 1H),8.25 (d, 1H), 7.93 (br.s, 1H), 7.80 (d, 1H), 7.83 (d, 1H), 7.40 (br.s,1H), 5.00 (s, 2H), 4.11 (t, 2H) 3.53 (s, 3H), 2.95-2.75 (m, 5H), 2.02(s, 3H), 1.97 (s, 3H), 1.35 (d, 9H).

Step 3

According to the general method for Boc deprotection, tert-butylN-methyl-N-[(6-{3-[2-(1,3,5-trimethyl-1H-pyrazol-4-yl)ethoxy]pyridin-2-yl}-[1,2,4]triazolo[4,3-a]pyridin-3-yl)methyl]carbamate(80 mg) was dissolved in dioxane (5 ml) and treated with a solution ofHCl in dioxane (4M, 5 ml). The solution was stirred at room temperaturefor 3 hr. The solvent was removed under reduced pressure and the residuetriturated with diethyl ether. The crude product was dissolved in waterand freeze-dried to provide the title compound as a light yellowhydrochloride salt (75 mg, 77%) LC-MS rt 9.2 min-MH⁺ 392. ¹H NMR (400MHz, DMSO-d6) δ 9.84 (br.s, 2H), 9.23 (s, 1H), 8.36 (d, 1H), 8.01 (d,1H), 7.94 (d, 1H), 7.76 (d, 1H), 7.54 (m, 1H), 4.84 (s, 2H), 4.21 (t,2H), 3.75 (s, 3H), 2.95 (t, 2H), 2.70 (s, 3H), 2.15 (s, 3H), 2.13 (s,3H).

Example 50

1-(5-(3,4-difluoro-2-(2-(1,3,5-trimethyl-1H-pyrazol-4-yl)ethoxy)phenyl)-1-methyl-1H-indazol-3-yl)-N-methylmethanamine

Intermediate 17 (140 mg, 0.42 mmol) was dissolved in a solution ofmethylamine in ethanol (33%, 10 ml) then stirred at room temperature for2 days. The mixture was evaporated under reduced pressure and theresidue redissolved in ethanol (10 ml) then treated with sodiumborohydride (37 mg, mmol) and stirred at room temperature for 1 h.Excess borohydride was quenched by addition of hydrochloric acid (1M, 4ml) and the mixture was evaporated under reduced pressure. The residuewas basified with sodium hydroxide solution (10N) and extracted with DCM(2×20 ml). The organic phase was dried (Na₂SO₄) and evaporated underreduced pressure. The crude product was purified by columnchromatography on silica by gradient elution with DCM/methanoliammonia(95:5:0-95:5:1-90:10:2). Fractions containing the desired product werecombined and evaporated under reduced pressure to give crude product,which was further purified by SCX chromography by elution with 2M NH₃ inmethanol. The basic eluent was evaporated to give the title compound asa colourless oil (110 mg, 60%). LC-MS rt 12.2 min (5-98%) MH⁺ 440; ¹HNMR (400 MHz, Chloroform-d) δ 7.81 (d, J=1.2 Hz, 1H), 7.46 (dd, J=8.6,1.7 Hz, 1H), 7.33 (d, J=8.5 Hz, 1H), 7.07 (ddd, J=8.3, 5.9, 2.2 Hz, 1H),6.93 (td, J=9.1, 7.2 Hz, 1H), 4.10 (s, 2H), 4.05 (s, 3H), 3.72 (t, J=7.6Hz, 2H), 3.55 (s, 3H), 2.57 (t, J=7.6 Hz, 2H), 2.53 (s, 1H), 2.50 (s,3H), 1.92 (s, 3H), 1.88 (s, 3H)

Example 51

1-(5-(3-fluoro-2-((2-(1,3,5-trimethyl-1H-pyrazol-4-yl)oct-7-yn-1-yl)oxy)phenyl)-1-methyl-1H-indazol-3-yl)-N,N-dimethylmethanamine

Intermediate 18 (48 mg, 0.13 mmol) and Intermediate 19 (52 mg, 0.22mmol) were dissolved in dimethylformamide (DMF). Cesium carbonate (62mg, 0.19 mmol) was added and the pale yellow mixture was stirred at 100°C. for 18 hr. The dark purple mixture obtained was diluted with EtOAc(40 mL), washed with water (2×50 mL), dried over Na₂SO₄, andconcentrated in vacuo to give a brown oil. The crude product waspurified by reversed-phase high-performance liquid chromatography byelution with 20-98% methanol in water (0.1% formic acid) over 18 min togive1-(5-(3-fluoro-2-((2-(1,3,5-trimethyl-1H-pyrazol-4-yl)oct-7-yn-1-yl)oxy)phenyl)-1-methyl-1H-indazol-3-yl)-N,N-dimethylmethanamineas a brownish orange solid (5.1 mg, 8%). LC-MS rt 8.5 min (5-98%) MH⁺516; ESI HRMS, found 516.3141 (C₃₁H₃₉N₅OF), MH⁺ requires 516.3139. ¹HNMR (CDCl₃, 400 MHz, 300 K) δ 7.91 (1H, s), 7.60 (1H, dd, J=8.7, 1.4Hz), 7.38 (1H, d, J=8.7 Hz), 7.19-7.08 (3H, m), 4.16 (2H, s), 4.11 (3H,s), 3.87 (1H, m), 3.62 (3H, s), 2.53 (6H, s), 2.19 (1H, dd, J=14.3, 9.1Hz), 1.96 (2H, td, J=6.9, 2.4 Hz), 1.94 (3H, s), 1.90 (3H, s), 1.89 (1H,t, J=2.6 Hz), 1.41-1.12 (6H, m).

Example 56

{([6-(2-{2-[1,5-dimethyl-3-(morpholine-4-carbonyl)-1H-pyrazol-4-yl]ethoxy}-4-fluorophenyl)-[1,2,4]triazolo[4,3-a]pyridin-3-yl]methyl}(methyl)amineStep 1

A solution of2-(3-(((tert-butoxycarbonyl)(methyl)amino)methyl)-[1,2,4]triazolo[4,3-a]pyridin-6-yl)-5-fluorophenylmethanesulfonate (Intermediate 12, 140 mg, 0.37 mmol) in DMF (3 mL) wasreacted4-{[4-(2-chloroethyl)-1,5-dimethyl-1H-pyrazol-3-yl]carbonyl}morpholine(153 mg, 0.056 mmol) and cesium carbonate (428 mg, 1.31 mmol) at 90° C.for 16 hr. The reaction mixture was then diluted with ethyl acetate, andwashed with water and brine, dried over sodium sulphate andconcentrated. The crude product was purified by preparative HPLC(NH₄HCO₃:CH₃CN) to give tert-butylN-({6-[2-(2-{1,5-dimethyl-3-[(morpholin-4-yl)carbonyl]-1H-pyrazol-4-yl}ethoxy)-4-fluorophenyl]-[1,2,4]triazolo[4,3-a]pyridin-3-yl}methyl)-N-methylcarbamate(27 mg, 12%). ¹H NMR (400 MHz, DMSO-d₆) δ 8.44 (s, 1H), 7.75 (d, 1H),7.50-7.30 (m, 2H), 7.11 (dd, 1H), 6.88 (td, 1H), 4.94 (s, 2H), 4.12 (t,2H), 3.70-3.40 (m, 9H), 2.87 (t, 2H), 2.79 (s, 3H), 1.98 (s, 3H), 1.34(s, 9H).

Step 2

According to the general method for Boc deprotection (method B),tert-butylN-({6-[2-(2-{1,5-dimethyl-3-[(morpholin-4-yl)carbonyl]-1H-pyrazol-4-yl}ethoxy)-4-fluorophenyl]-[1,2,4]triazolo[4,3-a]pyridin-3-yl}methyl)-N-methylcarbamate(27 mg, 0.046 mmol) was dissolved a solution of HCl in dioxane (4M, 2ml). The solution stirred at room temperature for 3 hr and wasevaporated under reduced pressure. The crude product was triturated withether then dissolved in water and freeze-dried to give the titlecompound (24 mg, 97%). hplc rt 7.5 min LC-MS MH⁺ 508; ¹H NMR (400 MHz,DMSO-d₆) δ 9.46 (s, 2H), 8.76 (s, 1H), 7.80 (d, 1H), 7.60-7.50 (m, 2H),7.13 (dd, 1H), 6.95 (td, 1H), 4.82 (t, 2H), 4.14 (t, 2H), 3.70-3.60 (m,5H), 3.55-3.45 (m, 6H), 2.87 (t, 2H), 2.70 (t, 2H), 2.03 (s, 3H)

Example 57

{[6-(2-{2-[1,5-dimethyl-3-(pyrrolidine-1-carbonyl)-1H-pyrazol-4-yl]ethoxy}-4-fluorophenyl)-[1,2,4]triazolo[4,3-a]pyridin-3-yl]methyl}(methyl)amineStep 1

2-(3-(((tert-butoxycarbonyl)(methyl)amino)methyl)-[1,2,4]triazolo[4,3-a]pyridin-6-yl)-5-fluorophenylmethanesulfonate (Intermediate 12, 20 mg, 0.05 mmol) was reacted with2-{1,5-dimethyl-3-[(pyrrolidin-1-yl)carbonyl]-1H-pyrazol-4-yl}ethan-1-ol(20 mg, 0.08 mmol) and cesium carbonate (43 mg, 0.13 mmol) in DMF (0.5ml) at 90° C. for 16 hr. The reaction mixture was cooled to RT, dilutedwith EtOAc and washed with water, brine, dried over Na₂SO₄ andconcentrated under reduced pressure. The crude was purified bypreparative TLC (3% MeOH-EtOAc) to afford tert-butylN-({6-[2-(2-{1,5-dimethyl-3-[(pyrrolidin-1-yl)carbonyl]-1H-pyrazol-4-yl}ethoxy)-4-fluorophenyl]-[1,2,4]triazolo[4,3-a]pyridin-3-yl}methyl)-N-methylcarbamate(5 mg, 15%). ¹H NMR (400 MHz, DMSO-d₆) δ 7.76 (d, 1H), 7.60 (m, 1H),7.41 (d, 1H), 7.35 (m, 1H), 7.14 (dd, 1H), 6.90 (td, 1H), 4.95 (s, 2H),4.13 (t, 2H), 3.7-3.6 (m, 5H), 3.40 (t, 2H), 2.93 (m, 2H), 2.79 (s, 3H),1.93 (s, 3H), 1.77 (s, 3H), 1.33 (s, 9H).

Step 2

According to the general method for Boc deprotection (method B),tert-butylN-({6-[2-(2-{1,5-dimethyl-3-[(pyrrolidin-1-yl)carbonyl]-1H-pyrazol-4-yl}ethoxy)-4-fluorophenyl]-[1,2,4]triazolo[4,3-a]pyridin-3-yl}methyl)-N-methylcarbamate(10 mg, 0.18 mmol) was treated with a solution of HCl in dioxane (4M, 1mL). The solution stirred at room temperature for 2 hr and wasevaporated under reduced pressure. The crude product was triturated withether, then dissolved in water and freeze dried to give the titlecompound (8 mg, 96%). hplc rt 8.2 min LC-MS MH⁺ 492; ¹H NMR (400 MHz,DMSO-d₆) δ 9.29 (s, 2H), 8.73 (s, 1H), 7.80 (d, 1H), 7.55-7.40 (m, 2H),7.16 (dd, 1H), 6.93 (td, 1H), 4.82 (s, 2H), 4.15 (t, 2H), 3.70 (s, 3H),3.39 (t, 2H), 2.95 (t, 2H), 2.71 (s, 3H), 2.03 (s, 3H), 1.79 (s, 3H).

Example 58

[(6-{5-fluoro-3-[2-(1,3,5-trimethyl-1H-pyrazol-4-yl)ethoxy]pyridin-2-yl}-[1,2,4]triazolo[4,3-a]pyridin-3-yl)methyl](methyl)amineStep 1

To a solution of tert-butylN-methyl-N-{[6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-yl]methyl}carbamate(Example 47 Step 1, 240 mg, 0.85 mmol) in dioxane (20 mL) and water (4mL) were added2-chloro-5-fluoro-3-[2-(1,3,5-trimethyl-1H-pyrazol-4-yl)ethoxy]pyridine(577 mg, 1.7 mmol) and potassium carbonate (350 mg, 2.5 mmol). Thereaction mixture was purged with argon for 10 min. Pd(dppf)Cl₂.DCM (69mg, 0.08 mmol) was added and the reaction mixture was heated at 100° C.overnight. The reaction mixture was then diluted with ethyl acetate andwashed with sat. NaHCO³, water and brine, dried over sodium sulphate andconcentrated. The crude was then purified by column-chromatography onsilica eluting with 4% MeOH in DCM. Prep HPLC purification (CH₃CN:NH4HCO3) afforded the product [tert-butylN-[(6-{(6-{5-fluoro-3-[2-(1,3,5-trimethyl-1H-pyrazol-4-yl)ethoxy]pyridin-2-yl}-[1,2,4]triazolo[4,3-a]pyridin-3-yl)methyl]-N-methylcarbamate(243 mg; 56%). ¹H NMR (400 MHz, DMSO-d₆) δ 9.6 (br.s, 1H), 9.0 (br. s,1H), 8.27 (s, 1H), 7:82-7.80 (m, 2H), 7.71 (d, 1H), 5.76 (s, 1H), 4.96(s, 2H), 4.16 (t, 2H), 3.53 (s, 3H), 2.89 (t, 2H), 2.76 (s, 3H), 2.02(s, 3H), 1.97 (s, 3H), 1.35 (s, 9H).

Step 2

According to the general method for Boc deprotection (method B),tert-butylN-[(6-{5-fluoro-3-[2-(1,3,5-trimethyl-1H-pyrazol-4-yl)ethoxy]pyridin-2-yl}-[1,2,4]triazolo[4,3-a]pyridin-3-yl)methyl]-N-methylcarbamate(40 mg, 0.08 mmol) was dissolved in a solution of HCl in dioxane (4M, 2ml). The solution stirred at room temperature for 2 hr and wasevaporated under reduced pressure. The crude product was triturated withether to give the crude product as a hydrochloride salt. Furtherpurification was carried out by SCX chromatography, the sample wasloaded in a methanolic solution, followed by elution with NH₃-MeOH toafford desired product as free base. The fraction was then treated with2M HCl in ether at RT for 30 min. The mixture was concentrated underreduced pressure to afford desired product as hydrochloride salt. (30mg, 93%). hplc rt 4.6 min LC-MS MH⁺ 410; ¹H NMR (400 MHz, DMSO-d₆) δ9.38 (s, 1H), 9.01 (s, 1H), 8.34 (s, 1H), 7.88 (s, 2H), 7.63 (m, 1H),4.81 (s, 2H), 4.15 (t, 2H), 3.60 (s, 3H), 2.85 (t, 2H), 2.73 (t, 2H),2.06 (s, 3H), 2.00 (s, 3H).

Example 60

[2-(5-{4-fluoro-2-[2-(1,3,5-trimethyl-1H-pyrazol-4-yl)ethoxy]phenyl}-1-methyl-1H-indazol-3-yl)ethyl](methyl)amineStep 1

A solution of tert-butylN-[2-(5-{4-fluoro-2-[2-(1,3,5-trimethyl-1H-pyrazol-4-yl)ethoxy]phenyl}-2H-indazol-3-yl)ethyl]carbamate(Intermediate 21, 27 mg, 0.05 mmol) in THF (0.7 mL) was treated withsodium hydride (50% dispersion in oil, 11 mg, 0.215 mmol) portionwise at0° C. and warmed to RT over 30 min. The mixture was recooled to at 0° C.before addition of iodomethane (0.013 mL, 0.213 mmol). Conversion wasincomplete hence a further charges of sodium hydride (50% dispersion inoil, 11 mg, 0.215 mmol) and iodomethane (0.013 mL, 0.213 mmol). wereadded and the reaction was stirred at rt for another 16 h. The reactionmixture was quenched with ice-water and extracted with EtOAc. Theorganic layer was washed with water, brine, dried over Na₂SO₄ andconcentrated under reduced pressure. Crude was purified over prep TLC(3% MeOH-DCM) to afford desired product, tert-butylN-[2-(5-{4-fluoro-2-[2-(1,3,5-trimethyl-1H-pyrazol-4-yl)ethoxy]phenyl}-1-methyl-1H-indazol-3-yl)ethyl]-N-methylcarbamate(12 mg; 42%) ¹H NMR (400 MHz, DMSO-d₆) δ 7.70 (s, 1H), 7.54 (d, 1H),7.41 (d, 1H), 7.33 (td, 1H), 6.99 (dd, 1H), 6.84 (td, 1H), 3.99 (m, 5H),3.69 (m, 5H), 3.06 (t, 2H), 2.89 (s, 3H), 2.59 (t, 2H), 1.90 (s, 6H),1.30-1.10 (m, 9H).

Step 2

According to the general method for Boc deprotection (method B)tert-butylN-[2-(5-{4-fluoro-2-[2-(1,3,5-trimethyl-1H-pyrazol-4-yl)ethoxy]phenyl}-1-methyl-1H-indazol-3-yl)ethyl]-N-methylcarbamate(12 mg, 0.02 mmol) was a solution of HCl in dioxane (4M, 2 mL). Thesolution stirred at room temperature for 2 hr and was evaporated underreduced pressure. The crude product was triturated with ether thendissolved in water and freezer dried to give the title compound as acolourless solid (8 mg, 90%). Hplc rt 6.7 min, LC-MS MH⁺ 436; ¹H NMR(400 MHz, DMSO-d₆) δ 8.53 (s, 2H), 7.76 (s, 1H), 7.59 (d, 1H), 7.45 (d,1H), 7.33 (td, 1H), 7.01 (dd, 1H), 6.86 (td, 1H), 4.03 (t, 2H),3.70-3.60 (m, 5H), 3.30 (t, 2H), 2.70-2.60 (m, 5H), 1.92 (s, 3H), 1.89(s, 3H).

Example 62

[2-(5-{4-fluoro-2-[2-(1,3,5-trimethyl-1H-pyrazol-4-yl)ethoxy]phenyl}-1H-indazol-3-yl)ethyl](methyl)amine

To a stirred solution of tert-butylN-[2-(5-{4-fluoro-2-[2-(1,3,5-trimethyl-1H-pyrazol-4-yl)ethoxy]phenyl}-2H-indazol-3-yl)ethyl]carbamate(Intermediate 21, 30 mg, 0.06 mmol) in THF (1 mL) was added LiAlH₄solution (2M in THF, 0.12 mL, 0.24 mmol) dropwise. The reaction mixturewas heated under reflux for 2 hr. The reaction mixture was cooled to 0°C. and quenched with solid sodium sulphate decahydrate. The mixture wasfiltered through Celite, washed with THF and the filtrate wasconcentrated under reduced pressure. The crude was purified over prepTLC (6% MeOH-DCM-NH3) to afford desired product. The fraction wastreated with 2M HCl in ether to afford title product as HCl salt (10 mg,49%). LC-MS rt 1.43 min MH⁺ 422; ¹H NMR (400 MHz, DMSO-d₆) δ 7.66 (s,1H), 7.46 (d, 1H), 7.30-7.28 (m, 2H), 6.92 (dd, 1H), 6.81 (td, 1H), 3.91(t, 2H), 3.48 (s, 3H), 3.30 (t, 2H), 3.24 (t, 2H), 2.66 (t, 2H), 2.60(s, 3H), 1.81 (s, 3H), 1.78 (s, 3H).

Example 63

[(6-{4-fluoro-2-[2-(1,3,5-trimethyl-1H-pyrazol-4-yl)ethoxy]phenyl}imidazo[1,2-a]pyridin-3-yl)methyl]dimethylamine

According to the general method for reductive amination,6-{4-fluoro-2-[2-(1,3,5-trimethyl-1H-pyrazol-4-yl)ethoxy]phenyl}imidazo[1,2-a]pyridine-3-carbaldehyde(Intermediate 20, 45 mg, 0.11 mmol) was dissolved in methanol (1 mL) andwas treated with dimethylamine solution (2M in THF, 0.11 mL, 0.22 mmol)followed by acetic acid (0.005 ml). The mixture was stirred at roomtemperature for 1 h before addition of solid sodium cyanoborohydride(10.9 mg, 0.17 mmol). The reaction mixture was stirred at roomtemperature overnight and was quenched with NaHCO₃ solution andextracted with DCM. The organic layer was dried over Na₂SO₄ andconcentrated under reduced pressure. The crude product was purified bypreparative TLC (3% MeOH in DCM) to afford title product (16 mg, 33%).Hplc rt 4.9 min, LC-MS MH⁺ 422; ¹H NMR (400 MHz, DMSO-d₆) δ 8.46 (s,1H), 7.56 (d, 1H), 7.51 (s, 1H), 7.41 (td, 1H), 7.30 (d, 1H), 7.04 (dd,1H), 6.89 (td, 1H), 4.00 (t, 2H), 3.73 (s, 2H), 3.51 (s, 3H), 2.68 (t,2H), 2.14 (s, 6H), 1.89 (s, 3H), 1.88 (s, 3H).

Example 68

Ethyl[(6-{4-fluoro-2-[2-(1,3,5-trimethyl-1H-pyrazol-4-yl)ethoxy]phenyl}imidazo[1,2-a]pyridin-3-yl)methyl]amine

According to the general method for reductive amination,6-{4-fluoro-2-[2-(1,3,5-trimethyl-1H-pyrazol-4-yl)ethoxy]phenyl}imidazo[1,2-a]pyridine-3-carbaldehyde(Intermediate 20, 45 mg, 0.11 mmol) was dissolved in methanol (1 mL) andwas treated with ethylamine solution (2M in THF, 0.11 mL, 0.22 mmol)followed by acetic acid (0.005 ml). The mixture was stirred at roomtemperature for 1 h before addition of solid sodium cyanoborohydride(10.9 mg, 0.17 mmol). The reaction mixture was stirred at roomtemperature overnight and was quenched with NaHCO₃ solution andextracted with DCM. The organic layer was dried over Na₂SO₄ andconcentrated under reduced pressure. The crude product was purified bypreparative TLC (3% MeOH in DCM) to afford title product (16 mg, 33%).Hplc rt 4.9 min, LC-MS MH⁺ 422; H NMR (400 MHz, DMSO-d₆) δ 8.52 (s, 1H),7.55 (d, 1H), 7.54 (s, 1H), 7.43 (td, 1H), 7.30 (d, 1H), 7.04 (dd, 1H),6.90 (td, 1H), 4.15 (s, 2H), 4.02 (t, 2H), 3.52 (s, 3H), 2.63 (m, 4H),1.91 (s, 3H), 1.90 (s, 3H), 1.04 (t, 3H).

Example 70

4-(2-{2-[3-(2-aminoethyl)imidazo[1,2-a]pyridin-6-yl]-5-fluorophenoxy}ethyl)-N,N,1,5-tetramethyl-1H-pyrazole-3-carboxamideStep 1

A solution of tert-butylN-{2-[6-(4-fluoro-2-hydroxyphenyl)imidazo[1,2-a]pyridin-3-yl]ethyl}carbamate(Intermediate 22 step 2, 65 mg, 0.14 mmol) in DMF (1 ml.) was reactedwith 4-(2-chloroethyl)-N,N,1,5-tetramethyl-1H-pyrazole-3-carboxamide(47.5 mg, 0.21 mmol) and cesium carbonate (157 mg, 0.48 mmol) at 80° C.for 16 hr. The reaction mixture was then diluted with DCM, and washedwith sat. NaHCO₃, water and brine, dried over sodium sulphate andconcentrated. This crude material was purified by prep TLC plate methodto give tert-butylN-{2-[6-(2-{2-[3-(dimethylcarbamoyl)-1,5-dimethyl-1H-pyrazol-4-yl]ethoxy}-4-fluorophenyl)imidazo[1,2-a]pyridin-3-yl]ethyl}carbamate(27 mg, 29%). ¹H NMR (400 MHz, DMSO-d₆) δ 8.34 (s, 1H), 7.50 (d, 1H),7.45 (t, 1H), 7.41 (s, 1H), 7.22 (d, 1H), 7.06 (dd, 1-H), 6.97 (dd, 1H),6.86 (td, 1H), 4.11 (t, 2H), 3.64 (s, 3H), 3.27 (t, 2H), 3.03 (s, 3H),3.02 (m, 2H), 2.90 (s, 3H), 2.84 (t, 2H), 1.94 (s, 3H), 1.30 (s, 9H).

Step 2

According to the general method for Boc deprotection (method B),tert-butylN-{2-[6-(2-{2-[3-(dimethylcarbamoyl)-1,5-dimethyl-1H-pyrazol-4-yl]ethoxy}-4-fluorophenyl)imidazo[1,2-a]pyridin-3-yl]ethyl}carbamate(100 mg, 0.18 mmol) was dissolved in dioxane (2 ml) and treated with asolution of HCl in dioxane (4M, 3 ml). The solution stirred at roomtemperature for 2 hr and was evaporated under reduced pressure (90 mg,99%). hplc rt 3.6 min LC-MS MH⁺ 465; ¹H NMR (400 MHz, DMSO-d₆) δ 14.6(br.s, 1H), 8.93 (s, 1H), 8.13 (m, 4H), 8.04 (d, 1H), 7.99 (d, 1H), 7.55(td, 1H), 7.17 (dd, 1H), 6.97 (td, 1H), 4.12 (t, 2H), 3.70 (s, 3H), 3.43(t, 2H), 3.19 (m, 2H), 3.09 (s, 3H), 2.90 (s, 3H), 2.86 (t, 2H), 2.07(s, 3H).

Example 71

[2-(6-{4-fluoro-2-[2-(1,3,5-trimethyl-1H-pyrazol-4-yl)ethoxy]phenyl}imidazo[1,2-a]pyridin-3-yl)ethyl](methyl)amineStep 1

A solution of tert-butylN-[2-(6-{4-fluoro-2-[2-(1,3,5-trimethyl-1H-pyrazol-4-yl)ethoxy]phenyl}imidazo[1,2-a]pyridin-3-yl)ethyl]carbamate(intermediate for Example 69) (30 mg, 0.059 mmol) in THF (1 mL) wastreated with sodium hydride (50% dispersion in oil. 14.2 mg, 0.30 mmol)portionwise at 0° C. and the mixture was stirred at RT for 30 min. Themixture was re-cooled before addition of iodomethane (0.018 ml, 0.30mmol) and was allowed to stir at RT for 3 days. The reaction mixture wasquenched with ice-water and extracted with EtOAc. The organic layer waswashed with water, brine, dried over Na₂SO₄ and concentrated underreduced pressure. The crude product was purified by prep TLC (3%MeOH-DCM) to afford desired product tert-butylN-[2-(6-{4-fluoro-2-[2-(1,3,5-trimethyl-1H-pyrazol-4-yl)ethoxy]phenyl}imidazo[1,2-a]pyridin-3-yl)ethyl]-N-methylcarbamate(14 mg, 31%) ¹H NMR (400 MHz, DMSO-d₆) δ 8.35 (s, 1H), 7.52 (td, 1H),7.41-7.36 (m, 2H), 7.25 (d, 1H), 7.04 (dd, 1H), 6.88 (td, 1H), 4.01 (t,2H), 3.52 (s, 3H), 3.48 (t, 2H), 3.25 (m, 2H), 3.12 (t, 2H), 2.79 (t,2H), 2.67 (s, 3H), 1.94 (s, 3H), 1.90 (s, 3H), 0.85 (s, 9H).

Step 2

According to the general method for Boc deprotection (method B)tert-butylN-[2-(6-{4-fluoro-2-[2-(1,3,5-trimethyl-1H-pyrazol-4-yl)ethoxy]phenyl}imidazo[1,2-a]pyridin-3-yl)ethyl]-N-methylcarbamate(14 mg, 0.027 mmol) was dissolved in dioxane (2 ml) and treated with asolution of HCl in dioxane (4M, 2 ml). The solution stirred at roomtemperature for 2 hr and was evaporated under reduced pressure. Thecrude product was triturated with ether, then dissolved in water andfreeze-dried to give the title compound as a colourless solid (10 mg,yield: 88%). hplc rt 7.5 min LC-MS MH⁺ 422; ¹H NMR (400 MHz, DMSO-d₆) δ14.6 (br.s, 1H), 9.12 (br. s, 2H), 8.96 (s, 1H), 8.17 (s, 1H), 8.00 (dd,2H), 7.56 (td, 1H), 7.14 (dd, 1H), 6.97 (td, 1H), 4.07 (t, 2H), 3.61 (s,3H), 3.48 (t, 2H), 3.28 (m, 2H), 2.73 (t, 2H), 2.66 (d, 3H), 2.03 (s,3H), 1.89 (s, 3H).

Example 72

[2-(6-{4-fluoro-2-[2-(1,3,5-trimethyl-1H-pyrazol-4-yl)ethoxy]phenyl}imidazo[1,2-a]pyridin-3-yl)ethyl]dimethylamine

A solution of2-(6-{4-fluoro-2-[2-(trimethyl-1H-pyrazol-4-yl)ethoxy]phenyl}imidazo[1,2-a]pyridin-3-yl)ethan-1-amine(Example 69, 24 mg, 0.054 mmol) in methanol (2 mL) was treated withformaldehyde solution (37% in water, 8 μL, 0.27 mmol). The reactionmixture was stirred at rt for 1 hour, before being cooled to 0° C. andtreated with sodium cyanoborohydride (10.2 mg, 0.16 mmol). The reactionmixture was stirred at rt for 16 hours before being diluted with DCM,washed with NaHCO₃ solution, dried over Na₂SO₄ and concentrated underreduced pressure. The crude material was purified using prep TLC to givethe title compound (10 mg, 42%). hplc rt 3.7 min LC-MS MH⁺ 436; ¹H NMR(400 MHz, DMSO-d₆) δ 8.33 (s, 1H), 7.51 (d, 1H), 7.45-7.35 (m, 2H), 7.24(d, 1H), 7.94 (dd, 1H), 6.88 (td, 1H), 4.01 (t, 2H), 3.52 (s, 3H), 3.02(t, 2H), 2.68 (t, 2H), 2.64 (t, 2H), 2.22 (s, 6H), 1.91 (s, 3H), 1.89(s, 3H).

Example 73

4-[2-(5-fluoro-2-{3-[2-(methylamino)ethyl]imidazo[1,2-a]pyridin-6-yl}phenoxy)ethyl]-N,N,1,5-tetramethyl-1H-pyrazole-3-carboxamideStep 1

A solution tert-butylN-{2-[6-(2-{2-[3-(dimethylcarbamoyl)-1,5-dimethyl-1H-pyrazol-4-yl]ethoxy}-4-fluorophenyl)imidazo[1,2-a]pyridin-3-yl]ethyl}carbamate(intermediate for Example 70) (55 mg, 0.097 mmol) in THF (2 mL) wastreated with sodium hydride (50% dispersion in oil. 23.4 mg, 0.49 mmol)portionwise at 0° C. and the mixture was stirred at RT for 30 min. Themixture was re-cooled before addition of iodomethane (0.03 ml, 0.49mmol) and was allowed to stir at RT for 3 days. The reaction mixture wasquenched with ice-water and extracted with EtOAc. The organic layer waswashed with water, brine, dried over Na₂SO₄ and concentrated underreduced pressure. The crude product was purified by prep TLC (3%MeOH-DCM) to afford desired tert-butylN-{2-[6-(2-{2-[3-(dimethylcarbamoyl)-1,5-dimethyl-1H-pyrazol-4-yl]ethoxy}-4-fluorophenyl)imidazo[1,2-a]pyridin-3-yl]ethyl}-N-methylcarbamate(30 mg, 53%) ¹H NMR (400 MHz, DMSO-d₆) δ 8.42 (s, 1H), 7.58 (d, 1H),7.45-7.30 (m, 3H), 7.08 (dd, 1H), 6.89 (td, 1H), 5.75 (s, 1H), 4.10 (t,2H), 3.66 (s, 3H), 3.49 (t, 2H), 3.33 (m, 2H), 3.14 (t, 2H), 3.06 (s,3H), 2.90 (s, 3H), 2.80 (t, 2H), 1.98 (s, 3H), 0.95 (s, 9H).

Step 2

According to the general method for Boc deprotection (method B),tert-butylN-{2-[6-(2-{2-[3-(dimethylcarbamoyl)-1,5-dimethyl-1H-pyrazol-4-yl]ethoxy}-4-fluorophenyl)imidazo[1,2-a]pyridin-3-yl]ethyl}-N-methylcarbamate(30 mg, 0.05 mmol) was dissolved in a solution of HCl in dioxane (4M, 5ml). The solution stirred at room temperature for 2 hr and wasevaporated under reduced pressure. The crude product was triturated withether then dissolved in water and freeze dried to give the titlecompound (22 mg, 88%). hplc rt 3.7 min LC-MS MH⁺ 479; ¹H NMR (400 MHz,DMSO-d₆) δ 14.7 (br.s, 1H), 9.01 (s, 2H), 8.95 (s, 1H), 8.15 (s, 1H),8.04 (d, 1H), 7.98 (d, 1H), 7.57 (dd, 1H), 7.17 (dd, 1H), 6.97 (td, 1H),4.15 (t, 2H), 3.70 (s, 3H), 3.50 (t, 2H), 3.29 (m, 2H), 3.09 (s, 3H),2.91 (s, 3H), 2.88 (t, 2H), 2.66 (t, 3H), 2.07 (s, 3H).

Example 74

[(6-{3-fluoro-2-[2-(1,3,5-trimethyl-1H-pyrazol-4-yl)ethoxy]phenyl}imidazo[1,2-a]pyridin-3-yl)methyl](methyl)amine

6-(3-fluoro-2-(2-(1,3,5-trimethyl-1H-pyrazol-4-yl)ethoxy)phenyl)imidazo[1,2-a]pyridine-3-carbaldehyde(Intermediate 26, 0.22 g, 0.56 mmol) was dissolved in a solution ofmethylamine in ethanol (33%, 10 mL) then stirred at room temperature for18 h. The mixture was evaporated under reduced pressure and theresidue-redissolved in ethanol (10 mL) then was added with sodiumborohydride (0.043 g, 1.12 mmol) and stirred at room temperature for 4h. Excess borohydride was quenched by addition of hydrochloric acid (1M,5 mL) and the mixture was evaporated under reduced pressure. The residuewas basified with sodium hydroxide solution (10 N) and extracted withDCM (3×30 mL). The organic phase was dried over Na₂SO₄ and evaporatedunder reduced pressure. The crude was purified by column chromatographyto afford the product which was further purified by SFC chromatographyby elution with 0.1 to 1.0% NH₃ in methanol. The basic eluent wasevaporated to obtain product as viscous oil. The product was dissolvedin 4 M HCl in dioxane (5 mL) and stirred at room temperature for 15 min.The reaction mixture was then concentrated under reduced pressure. Theresidue was purified by trituration with diethylether (2×5 mL) followedn-pentane (2×5 mL) to afford the title compound as an off-white solid(70 mg, 52%). LC-MS MH⁺ 408; ¹H NMR (400 MHz, DMSO-d₆) δ 9.87 (brs, 2H),9.21 (s, 1H), 8.42 (s, 1H), 8.01-7.87 (m, 2H), 7.54 (d, J=7.7 Hz, 1H),7.44 (t, J=10.0 Hz, 1H), 7.29 (q, J=7.1 Hz, 1H), 4.72 (d, J=5.5 Hz, 2H),3.92 (t, J=6.8 Hz, 2H), 3.63 (s, 3H), 2.60 (m, 5H), 2.01 (s, 3H), 1.93(s, 3H).

Example 75

[(6-{3-fluoro-2-[2-(1,3,5-trimethyl-1H-pyrazol-4-yl)ethoxy]phenyl}imidazo[1,2-a]pyridin-3-yl)methyl]dimethylamine

A solution of6-(3-fluoro-2-(2-(1,3,5-trimethyl-1H-pyrazol-4-yl)ethoxy)phenyl)imidazo[1,2-a]pyridine-3-carbaldehyde(Intermediate 26, 0.22 g, 0.56 mmol) in THF (8 mL) was treated withdimethylamine (1.4 mL of 2M solution in THF, 2.8 mmol) and aceticacid-(0.19 mL, 3.36 mmol) was stirred at room temperature for 30 min.Sodium triacetoxyborohydride (0.48 g, 2.24 mmol) and DCE (5 mL) wasadded to the reaction mixture, and stirred at room temperature for 18 h.After completion of the reaction, the reaction mixture was quenched withthe addition of saturated Na₂CO₃ solution (10 mL) and extracted with DCM(3×20 mL). The combined organic layer was dried over Na₂SO₄ andconcentrated under reduced pressure. The crude product was purified bycolumn chromatography to afford the product which was further purifiedby SFC chromatography by elution with 0.1 to 1.0% NH₃ in methanol. Theproduct was dissolved in 4 M HCl in dioxane (5 mL) and stirred at roomtemperature for 15 min. The reaction mixture was then concentrated underreduced pressure. The residue was purified by trituration with diethylether. (2×5 mL) followed n-pentane (2×5 mL) to afford the title compound(60m g, 24%). LC-MS MH⁺ 408; ¹H NMR (400 MHz, DMSO-d₆) δ 11.70 (brs,1H), 9.24 (s, 1H), 8.49 (s, 1H), 7.93 (q, J=9.3 Hz, 2H), 7.55 (d, J=7.7Hz, 1H), 7.43 (t, J=9.9 Hz, 1H), 7.33-7.23 (m, 1H), 4.87 (s, 2H), 3.89(t, J=6.9 Hz, 2H), 3.60 (s, 3H), 2.82 (s, 6H), 2.57 (t, J=6.9 Hz, 2H),1.99 (s, 3H), 1.89 (s, 3H).

Example 76

4-[2-(2-{3-[2-(dimethylamino)ethyl]imidazo[1,2-a]pyridin-6-yl}-5-fluorophenoxy)ethyl]-N,N,1,5-tetramethyl-1H-pyrazole-3-carboxamide

The product from Example 70(4-(2-{2-[3-(2-aminoethyl)imidazo[1,2-a]pyridin-6-yl]-5-fluorophenoxy}ethyl)-N,N,1,5-tetramethyl-1H-pyrazole-3-carboxamidehydrochloride salt, 90 mg, 0.18 mmol) was dissolved in methanol (2.0 mL)and treated with formaldehyde solution (37% in water, 0.8 mL, 0.9 mmol).The reaction mixture was stirred at rt for 1 hour, before being cooledto 0° C. and treated with sodium cyanoborohydride (33.9 mg, 0.54 mmol).After being stirred at rt for 16 hours, the reaction mixture was dilutedwith DCM and washed with NaHCO₃ solution. The organic phase was driedover Na₂SO₄ and concentrated under reduced pressure. The crude materialwas purified using prep TLC to give the title compound (50 mg, 56%).hplc rt 4.5 min LC-MS MH⁺ 493; ¹H NMR (400 MHz, DMSO-d₆) δ 8.32 (s, 1H),7.50 (d, 1H), 7.45 (d, 1H), 7.42 (s, 1H), 7.22 (dd, 1H), 7.07 (dd, 1H),6.87 (td, 1H), 4.11 (t, 2H), 3.64 (s, 3H), 3.04 (s, 3H), 3.01 (t, 2H),2.90 (s, 3H), 2.84 (t, 2H), 2.67 (t, 2H), 1.94 (s, 3H).

Example 77

4-[2-(5-fluoro-2-{3-[(methylamino)methyl]imidazo[1,2-a]pyridin-6-yl}phenoxy)ethyl]-N,N,1,5-tetramethyl-1H-pyrazole-3-carboxamideStep 1

A solution of tert-butylN-{[6-(4-fluoro-2-hydroxyphenyl)imidazo[1,2-a]pyridin-3-yl]methyl}-N-methylcarbamate(intermediate 24, 400 mg, 1.08 mmol) in DMF (10 mL) was reacted with4-(2-chloroethyl)-N,N,1,5-tetramethyl-1H-pyrazole-3-carboxamide (47.5mg, 0.21 mmol) and cesium carbonate (1.23 g, 3.77 mmol) at 80° C. for 16hr. The reaction mixture was then diluted with DCM, and washed with sat.NaHCO₃, water and brine, dried over sodium sulphate and concentrated.This crude material was purified by prep hplc by elution with NH₄HCO₃buffer and CH³CN/water. to give tert-butylN-{[6-(2-{2-[3-(dimethylcarbamoyl)-1,5-dimethyl-1H-pyrazol-4-yl]ethoxy}-4-fluorophenyl)imidazo[1,2-a]pyridin-3-yl]methyl}-N-methylcarbamate(120 mg, 20%). ¹H NMR (400 MHz, DMSO-d₆) δ 8.50-8.30 (m, 2H), 7.63 (s,1H), 7.57 (d, 1H), 7.30-7.20 (m, 2H), 7.06 (dd, 1H), 6.84 (td, 1H), 4.78(s, 2H), 4.09 (t, 2H), 3.63 (s, 3H), 3.03 (s, 3H), 2.89 (s, 3H), 2.68(m, 2H), 1.89 (s, 3H), 1.36 (s, 9H).

Step 2

According to the general method for Boc deprotection (method B),tert-butylN-{[6-(2-{2-[3-(dimethylcarbamoyl)-1,5-dimethyl-1H-pyrazol-4-yl]ethoxy}-4-fluorophenyl)imidazo[1,2-a]pyridin-3-yl]methyl}-N-methylcarbamate(90 mg, 0.16 mmol) was dissolved in dioxane (2 ml) and treated with asolution of HCl in dioxane (4M, 3 ml). The solution stirred at roomtemperature for 3 hr and was evaporated under reduced pressure to givethe title compound as a yellow solid (74 mg, 100%). hplc rt 3.8 minLC-MS MH⁺ 465; ¹H NMR (400 MHz, DMSO-d₆) δ 9.41 (br.s, 2H), 9.11 (s,1H), 8.31 (s, 1H), 8.02 (d, 1H), 7.94 (d, 1H), 7.66 (td, 1H), 7.17 (dd,1H), 6.99 (td, 1H), 4.72 (s, 2H), 4.13 (t, 2H), 3.67 (s, 3H), 3.55 (s,3H), 3.09 (s, 3H), 2.91 (s, 3H), 2.85 (t, 2H), 2.62 (d, 3H), 2.05 (s,3H).

Example 78

4-[2-(2-{3-[(dimethylamino)methyl]imidazo[1,2-a]pyridin-6-yl}-5-fluorophenoxy)ethyl]-N,N,1,5-tetramethyl-1H-pyrazole-3-carboxamide

The product from Example 774-[2-(5-fluoro-2-{3-[(methylamino)methyl]imidazo[1,2-a]pyridin-6-yl}phenoxy)ethyl]-N,N,1,5-tetramethyl-1H-pyrazole-3-carboxamide(50 mg, 0.05 mmol) was dissolved in methanol (1.0 mL) and treated withformaldehyde solution (37% in water, 0.04 mL, 0.50 mmol). The reactionmixture was stirred at rt for 1 hour, before being cooled to 0° C. andtreated with sodium cyanoborohydride (18.7 mg, 0.30 mmol). After beingstirred at rt for 16 hours, the reaction mixture was diluted with DCMand washed with NaHCO₃ solution. The organic phase was dried over Na₂SO₄and concentrated under reduced pressure. The crude material was purifiedusing prep TLC by elution with DCM: methanol (94:6) to give the titlecompound (25 mg, 48%). hplc rt 5.0 min LC-MS MH⁺ 479; ¹H NMR (400 MHz,DMSO-d₆) δ 8.46 (s, 1H), 8.27 (s, 1H), 7.5-7.2 (m, 2H), 7.41 (t, 1H),7.27 (dd, 1H), 7.07 (dd, 1H), 6.88 (td, 1H), 4.10 (t, 2H), 3.73 (s, 1H),3.64 (s, 3H), 3.04 (s, 2H), 2.90 (s, 2H), 2.65 (d, 3H), 2.85 (t, 2H),2.14 (s, 6H), 1.91 (s, 3H).

Example 79

2-(6-{3-fluoro-2-[2-(1,3,5-trimethyl-1H-pyrazol-4-yl)ethoxy]phenyl}imidazo[1,2-a]pyridin-3-yl)ethan-1-amineStep 1

A solution of tert-butyl (2-(6-(3-fluoro-2-hydroxyphenyl) imidazo [1,2-a] pyridin-3-yl) ethyl) carbamate (Intermediate 27, 0.5 g, 1.3 mmol)in THF (25 mL), PPh₃ (0.68 mg, 2.60 mmol) and2-(1,3,5-trimethyl-1H-pyrazol-4-yl)ethan-1-ol (0.41 g, 2.60 mmol) in THF(4 mL) was treated dropwise with di-isopropyl azodicarboxylate (0.51 mL,2.60 mmol) at 0° C. The mixture was warmed to room temperature for 16hr, then concentrated under reduced pressure. The crude product waspurified by column chromatography to afford tert-butyl(2-(6-(3-fluoro-2-(2-(1,3,5-trimethyl-1H-pyrazol-4-yl)ethoxy)phenyl)imidazo[1,2-a]pyridin-3-yl)ethyl)carbamate (350 mg, 51%). ¹H NMR (400 MHz,DMSO-d₆) δ 8.41 (s, 1H), 7.55 (dd, J=14.2, 9.2 Hz, 1H), 7.43 (s, 1H),7.38-7.16 (m, 4H), 7.01-6.97 (m, 1H), 3.82 (t, J=7.3 Hz, 2H), 3.46 (d,J=5.9 Hz, 3H), 3.32 (s, 2H), 3.04-3.00 (m, 2H), 2.60-2.46 (m, 2H), 1.84(d, J=6.1 Hz, 6H), 1.30 (s, 9H).

Step 2

According to the general method for Boc deprotection (method B), asolution of tert-butyl(2-(6-(3-fluoro-2-(2-(1,3,5-trimethyl-1H-pyrazol-4-yl)ethoxy)phenyl)imidazo [1,2-a]pyridin-3-yl)ethyl)carbamate (0.1 g, 0.19 mmol) inDCM (10 mL), was treated with HCl in dioxane (4M, 0.5 mL) and stirred atroom temperature for 2 hr. The reaction mixture was concentrated underreduced pressure and the residue was purified by trituration with etherand n-pentane, then again purified by SFC chromatography to afford thetitle compound (40 mg, 50%). LC-MS MH⁺ 408; ¹H NMR (400 MHz, DMSO-d₆) δ8.82 (s, 1H), 8.07 (s, 1H), 7.90 (d, J=15.6 Hz, 3H), 7.45-7.40 (m, 1H),7.37-7.23 (m, 2H), 3.90 (t, J=6.9 Hz, 3H), 3.48 (s, 3H), 3.34 (t, J=7.1Hz, 2H), 3.22-3.08 (m, 2H), 2.55 (t, J=6.9 Hz, 2H), 1.94 (s, 3H), 1.82(s, 3H)

Example 80

[2-(6-{3-fluoro-2-[2-(1,3,5-trimethyl-1H-pyrazol-4-yl)ethoxy]phenyl}imidazo[1,2-a]pyridin-3-yl)ethyl](methyl)amineStep 1

A solution of tert-butyl(2-(6-bromoimidazo[1,2-a]pyridin-3-yl)ethyl)(methyl)carbamate(Intermediate 28, 140 mg, 0.36 mmol) and2-(1,3,5-trimethyl-1H-pyrazol-4-yl)ethan-1-ol (110 mg, 0.72 mmol) intoluene (10 mL), was treated with cyanomethylene tributylphosphorane,130 mg, 0.54 mmol) and the reaction mixture was refluxed for 5 hr. Aftercompletion of the reaction, the reaction mixture was concentrated underreduced pressure and the residue was purified by column chromatographyusing to afford tert-butyl(2-(6-(3-fluoro-2-(2-(1,3,5-trimethyl-1H-pyrazol-4-yl)ethoxy)phenyl)imidazo[1,2-a]pyridin-3-yl)ethyl)(methyl)-carbamate(90 mg, 48%). ¹H NMR (400 MHz, DMSO-d₆) δ 8.41 (d, J=10.7 Hz, 1H), 7.55(d, J=9.9 Hz, 1H), 7.44-7.16 (m, 4H), 4.09 (q, J=5.3 Hz, 1H), 3.81 (t,J=7.4 Hz, 2H), 3.48 (s, 3H), 3.19-3.08 (m, 4H), 2.79 (s, 3H), 2.73 (s,2H), 1.85 (d, J=9.4 Hz, 6H), 1.28 (s, 3H), 0.99 (s, 6H).

Step 2

According to the general method for Boc deprotection (method B),tert-butyl(2-(6-(3-fluoro-2-(2-(1,3,5-trimethyl-1H-pyrazol-4-yl)ethoxy)phenyl)imidazo[1,2-a]pyridin-3-yl)ethyl)(methyl)carbamate (90 mg, 0.17 mmol) was dissolved in DCM (10 mL), and treatedwith HCl in dioxane (4M, 0.2 mL) was added and stirred at roomtemperature for 1 hr. After completion of the reaction, the reactionmixture was concentrated under reduced pressure and the residue waspurified by trituration with ether to give the title compound (74 mg,94%) as a brown solid. LC-MS rt 2.0 min, MH⁺ 422. ¹H NMR (400 MHz,DMSO-d₆) δ 9.23 (s, 2H), 8.98 (s, 1H), 8.21 (s, 1H), 7.95 (s, 2H),7.50-7.35 (m, 2H), 7.28 (td, J=8.0, 5.0 Hz, 1H), 3.94 (t, J=6.7 Hz, 2H),3.62-3.43 (m, 6H), 3.28 (p, J=7.2 Hz, 2H), 2.58 (dt, J=16.4, 6.1 Hz,6H), 1.91 (s, 3H).

Example 81

2-(6-{3,4-difluoro-2-[2-(1,3,5-trimethyl-1H-pyrazol-4-yl)ethoxy]phenyl}imidazo[1,2-a]pyridin-3-yl)ethan-1-amineStep 1

A solution of tert-butyl(2-(6-(3,4-difluoro-2-hydroxyphenyl)imidazo[1,2-a]pyridin-3-yl)ethyl)carbamate(Intermediate 29, 90 mg, 0.23 mmol) and2-(1,3,5-trimethyl-1H-pyrazol-4-yl)ethan-1-ol (71 mg, 0.46 mmol) intoluene (10 mL) was treated with cyanomethylene tributyl-phophorane (83mg, 0.34 mmol) and the reaction mixture was refluxed for 5 hr. Thereaction mixture was concentrated under reduced pressure. The residuewas purified by column chromatography to afford tert-butyl(2-(6-(3,4-difluoro-2-(2-(1,3,5-trimethyl-1H-pyrazol-4-yl)ethoxy)phenyl)imidazo[1,2-a] pyridin-3-yl) ethyl)carbamate (38 mg, 31%). ¹H NMR (400MHz, CDCl₃) δ 8.06 (s, 1H), 7.63 (d, J=9.3 Hz, 1H), 7.51 (s, 1H), 7.25(s, 1H), 7.12-7.05 (m, 1H), 7.05-6.94 (m, 1H), 5.31 (s, 2H), 3.96 (t,J=7.1 Hz, 1H), 3.69 (d, J=9.6 Hz, 1H), 3.52 (d, J=6.0 Hz, 3H), 3.11-3.03(m, 2H), 2.64-2.60 (m, 2H), 2.03 (s, 3H), 1.91 (s, 3H), 1.43 (s, 9H).

Step 2

According to the general method for Boc deprotection (method B), asolution of tert-butyl(2-(6-(3,4-difluoro-2-(2-(1,3,5-trimethyl-1H-pyrazol-4-yl)ethoxy)phenyl)imidazo[1,2-a]pyridin-3-yl)ethyl)carbamate(38 mg, 0.07 mmol) in DCM (3 mL), was treated with HCl in dioxane (4M, 1mL) and stirred at room temperature for 1 hr. The reaction mixture wasconcentrated under reduced pressure and the residue was triturated withdiethyl ether followed by n-pentane to give the title compound (11 mg,37%) as a brown solid. LC-MS rt 1.6 min, MH⁺ 426. ¹H NMR (400 MHz,DMSO-d₆) δ 8.96 (s, 1H), 8.26 (brs, 2H), 8.18 (s, 1H), 8.00-7.89 (m,2H), 7.39 (dd, J=8.7, 6.2 Hz, 2H), 4.01 (t, J=6.8 Hz, 2H), 3.54 (s, 3H),3.43 (t, J=7.1 Hz, 2H), 3.19 (q, J=6.4 Hz, 2H), 2.61 (t, J=6.8 Hz, 2H),1.99 (s, 3H), 1.90 (s, 3H).

Example 82

[2-(6-{3,4-difluoro-2-[2-(1,3,5-trimethyl-1H-pyrazol-4-yl)ethoxy]phenyl}imidazo[1,2-a]pyridin-3-yl)ethyl](methyl)amineStep 1

A solution of tert-butyl(2-(6-(3,4-difluoro-2-hydroxyphenyl)imidazo[1,2-a]pyridin-3-yl)ethyl)(methyl)carbamate(Intermediate 28, 80 mg, 0.19 mmol) and2-(1,3,5-trimethyl-1H-pyrazol-4-yl)ethan-1-ol (61 mg, 0.39 mmol) intoluene (10 mL) was treated with cyanomethylene tributylphosphorane (68mg, 0.28 mmol) and the reaction mixture was refluxed for 5 hr. Thereaction mixture was concentrated under reduced pressure. The residuewas purified by column chromatography to afford tert-butyl(2-(6-(3,4-difluoro-2-(2-(1,3,5-trimethyl-1H-pyrazol-4-yl)ethoxy)phenyl)imidazo[1,2-a] pyridin-3-yl) ethyl) (methyl) carbamate (60 mg, 56%). ¹HNMR (400 MHz, CDCl₃) δ 8.24 (s, 1H), 7.99 (s, 1H), 7.60 (s, 1H), 7.48(s, 1H), 7.13 (s, 1H), 6.98 (q, J=9.0 Hz, 1H), 3.91 (t, J=7.5 Hz, 2H),3.56 (d, J=12.5 Hz, 2H), 3.10 (s, 2H), 2.85 (d, J=17.6 Hz, 3H), 2.65 (t,J=7.5 Hz, 2H), 2.02 (s, 3H), 1.90 (s, 3H), 1.40 (s, 3H), 1.26 (s, 9H).

Step 2

According to the general method for Boc deprotection (method B), asolution of tert-butyl(2-(6-(3,4-difluoro-2-(2-(1,3,5-trimethyl-1H-pyrazol-4-yl)ethoxy)phenyl)imidazo[1,2-a]pyridin-3-yl)ethyl)(methyl) carbamate (60 mg, 0.11 mmol) in DCM (10 mL), was treated withHCl in dioxane (4M, 2 mL) and stirred at room temperature for 1 hr. Thereaction mixture was concentrated under reduced pressure and the residuewas triturated with diethyl ether to give the title compound (41 mg,85%) as a brown solid. LC-MS rt 1.6 min, MH⁺ 440. 1H NMR (400 MHz,DMSO-d6) δ 9.25-9.18 (m, 2H), 8.98 (s, 1H), 8.20 (s, 1H), 7.99-7.89 (m,2H), 7.46-7.32 (m, 2H), 4.01 (t, J=6.8 Hz, 1H), 3.75-3.43 (m, 5H),3.29-3.24 (m, 2H), 2.60-2.57 (m, 5H), 1.99 (s, 3H), 1.89 (s, 3H).

Example 83

4-[2-(5-fluoro-2-{3-[(methylamino)methyl]imidazo[1,2-a]pyridin-6-yl}phenoxy)ethyl]-1,5-dimethyl-1H-pyrazole-3-carboxylicacid

Step 1

A solution of tert-butylN-{[6-(4-fluoro-2-hydroxyphenyl)imidazo[1,2-a]pyridin-3-yl]methyl}-N-methylcarbamate(intermediate 24, 180 mg, 0.48 mmol) in DMF (1.5 mL) was reacted withmethyl 4-(2-chloroethyl)-1,5-dimethyl-1H-pyrazole-3-carboxylate (188 mg,0.87 mmol) and cesium carbonate (550 mg, 1.7 mmol) at 90° C. for 16 hr.The reaction mixture was then diluted with ethyl acetate, and washedwith sat. NaHCO₃, water and brine, dried over sodium sulphate andconcentrated. This crude material was purified by prep TLC by elutionwith DCM:methanol (95:5) to give methyl4-(2-{2-[3-({[(tert-butoxy)carbonyl]-(methyl)amino}methyl)imidazo[1,2-a]pyridin-6-yl]-5-fluorophenoxy}ethyl)-1,5-dimethyl-1H-pyrazole-3-carboxylate(75 mg, 28%). ¹H NMR (400 MHz, DMSO-d₆) δ 8.5 (br.s, 1H), 7.62 (s, 1H),7.56 (d, 1H), 7.32 (dd, 1H), 7.24 (d, 1H), 7.08 (dd, 1H), 6.83 (td, 1H),5.76 (s, 2H), 4.70 (t, 2H), 4.10 (t; 2H), 3.71 (s, 3H), 3.66 (s, 3H),3.00 (t, 2H), 2.67 (s, 3H), 2.00 (s, 3H), 1.33 (s, 9H).

Alternative Step 1

A solution of tert-butylN-{[6-(4-fluoro-2-hydroxyphenyl)imidazo[1,2-a]pyridin-3-yl]methyl}-N-methylcarbamate(intermediate 24, 1.0 g, 2.7 mmol) and methyl4-(2-hydroxyethyl)-1,5-dimethyl-1H-pyrazole-3-carboxylate (1.06 g, 5.4mmol) in toluene (10 mL) was treated with cyanomethylenetributylphosphorane (1.4 mL, 5.4 mmol) at 100° C. for 16 hr. Thereaction mixture was then diluted with ethyl acetate, and washed withwater and brine, dried over sodium sulphate and concentrated. This crudematerial was purified by column chromatography by elution withDCM:methanol (95:5) to give methyl4-(2-{2-[3-({[(tert-butoxy)carbonyl]-(methyl)amino}methyl)imidazo[1,2-a]pyridin-6-yl]-5-fluorophenoxy}ethyl)-1,5-dimethyl-1H-pyrazole-3-carboxylate (1.2 g, 81%). ¹H NMR (400MHz, CDCl₃) δ 8.44 (br.s, 1H), 7.57 (s, 1H), 7.51 (d, 1H), 7.20-7.15 (m,2H), 6.74 (dd, 1H), 6.60 (td, 1H), 4.77 (t, 2H), 4.14 (t, 2H), 3.89 (s,3H), 3.73 (s, 3H), 3.07 (t, 2H), 2.73 (s, 3H), 1.92 (s, 3H), 1.31 (s,9H).

Step 2

A solution of methyl4-(2-{2-[3-({[(tert-butoxy)carbonyl]-(methyl)amino}methyl)imidazo-[1,2-a]pyridin-6-yl]-5-fluorophenoxy}ethyl)-1,5-dimethyl-1H-pyrazole-3-carboxylate(40 mg, 0.07 mmol) in THE-water (4:1, 1.5 mL) was cooled at 0° C. andtreated with a solution of lithium hydroxide (6.1 mg, 0.14 mmol) inethanol (0.02 mL) at 0° C. The resulting mixture was stirred at rt for16 hr. The reaction mixture was evaporated under reduced pressure, thecrude reaction mixture was acidified with sat citric acid solution andextracted with DCM. The final organic layer was dried over sodiumsulphate and concentrated to afford desired product4-(2-{2-[3-({[(tert-butoxy)carbonyl](methyl)amino}methyl)imidazo[1,2-a]pyridin-6-yl]-5-fluorophenoxy}ethyl)-1,5-dimethyl-1H-pyrazole-3-carboxylicacid as an off-white solid (35 mg, 90%). ¹H NMR (400 MHz, DMSO-d₆) δ12.3 (br.s, 1H), 8.50 (s, 1H), 7.62 (s, 1H), 7.57 (d, 1H), 7.33 (dd,1H), 7.26 (dd, 1H), 7.11 (d, 1H), 6.84 (td, 1H), 4.76 (s, 2H), 4.10 (t,2H), 3.66 (s, 3H), 3.00 (t, 2H), 2.68 (s, 3H), 1.87 (s, 3H), 1.31 (s,9H).

Step 3

According to the general method for Boc deprotection (method B)4-(2-{2-[3-({[(tert-butoxy)carbonyl](methyl)amino}methyl)imidazo[1,2-a]pyridin-6-yl]-5-fluorophenoxy}ethyl)-1,5-dimethyl-1H-pyrazole-3-carboxylicacid (35 mg, 0.06 mmol) was dissolved in a solution of HCl in dioxane(4M, 1 mL). The solution stirred at room temperature for 3 hr and wasevaporated under reduced pressure. The crude product was dissolved inwater and freeze dried to give the title compound as alight brown solid(24 mg, 84%). hplc rt 6.8 min LC-MS MH⁺ 438; ¹H NMR (400 MHz, DMSO-d₆) δ9.26 (br.s, 2H), 9.02 (s, 1H), 8.25 (s, 1H), 7.89 (dd, 2H), 7.62 (dd,1H), 7.20 (dd, 1H), 6.98 (td, 1H), 4.70 (t, 2H), 4.14 (t, 2H), 3.72 (s,3H), 3.01 (t, 2H), 2.62 (t, 3H), 2.04 (s, 3H).

Example 84

{4-[2-(5-fluoro-2-{3-[(methylamino)methyl]imidazo[1,2-a]pyridin-6-yl}phenoxy)ethyl]-1,5-dimethyl-1H-pyrazol-3-yl}methanolStep 1

A solution of methyl4-(2-{2-[3-({[(tert-butoxy)carbonyl]-(methyl)amino}methyl)imidazo-[1,2-a]pyridin-6-yl]-5-fluorophenoxy}ethyl)-1,5-dimethyl-1H-pyrazole-3-carboxylate(Example 83 step 1 intermediate, 50 mg, 0.09 mmol) in THF (2 mL) wascooled at 0° C. and treated with a solution of LiAlH₄ (2M in THF, 0.09ml, 0.045 mmol). The resulting mixture was stirred at 0° C. for 2 hr.the reaction mixture was quenched with sodium sulfate decahydrate. Thereaction mixture was filtered through Celite bed, which was washed withethyl acetate. The filtrate was dried over Na₂SO₄ and evaporated underreduced pressure. The crude product was purified by prep TLC (5%MeOH/DCM) to give tert-butylN-{[6-(4-fluoro-2-{2-[3-(hydroxymethyl)-1,5-dimethyl-1H-pyrazol-4-yl]ethoxy}-phenyl)imidazo[1,2-a]pyridin-3-yl]methyl}-N-methylcarbamateas an off-white solid (22 mg, 47%). ¹H NMR (400 MHz, DMSO-d₆) 7.61 (s,1H), 7.56 (d, 1H), 7.32 (m, 2H), 7.03 (d, 1H), 6.85 (td, 1H), 4.77 (s,2H), 4.25 (d, 2H), 4.07 (t, 2H), 3.62 (s, 3H), 2.76 (t, 2H), 2.67 (s,3H), 1.88 (s, 3H), 1.33 (s, 9H).

Step 2

According to the general method for Boc deprotection (method B),tert-butylN-{[6-(4-fluoro-2-{2-[3-(hydroxymethyl)-1,5-dimethyl-1H-pyrazol-4-yl]ethoxy}-phenyl)imidazo[1,2-a]pyridin-3-yl]methyl}-N-methylcarbamate(20 mg, 0.04 mmol) was dissolved in a solution of HCl in dioxane (4M, 1ml). The solution stirred at room temperature for 3 hr and wasevaporated under reduced pressure. The crude product was dissolved inwater and freeze-dried to give the title compound as a light brown solid(10 mg, 62%). hplc rt 5.3 min LC-MS MH⁺ 424; ¹H NMR (400 MHz, DMSO-d₆) δ9.75 (br.s, 2H), 9.19 (s, 1H), 8.41 (s, 1H), 8.02 (d, 1H), 7.99 (d, 2H),7.74 (dd, 1H), 7.30 (dd, 1H), 7.13 (s, 1H), 6.97 (td, 1H), 4.73 (t, 2H),4.27 (s, 2H), 4.14 (t, 2H), 3.64 (s, 3H), 2.81 (t, 2H), 2.62 (t, 3H),2.03 (s, 3H).

Example 85

4-[2-(5-fluoro-2-{3-[(methylamino)methyl]imidazo[1,2-a]pyridin-6-yl}phenoxy)ethyl]-1,5-dimethyl-1H-pyrazole-3-carboxamideStep 1

A solution of4-(2-{2-[3-({[(tert-butoxy)carbonyl](methyl)amino}methyl)imidazo[1,2-a]pyridin-6-yl]-5-fluorophenoxy}ethyl)-1,5-dimethyl-1H-pyrazole-3-carboxylicacid (Example 83 step 2, 55 mg, 0.10 mmol) in DMF (2 mL) was treatedwith triethylamine (0.04 mL, 0.3 mmol), ammonium chloride (6.6 mg, 0.12mmol), hydroxybenztriazole 17.6 mg, 0.13 mmol) and EDCI (24.9 mg, 0.13mmol). The reaction mixture was stirred at rt for 16 hrs, diluted withDCM and washed with sat. NaHCO₃, water and brine, dried over sodiumsulphate and concentrated. The crude product was purified over prep TLC(5% MeOH/DCM) to give tert-butylN-[(6-{2-[2-(3-carbamoyl-1,5-dimethyl-1H-pyrazol-4-yl)ethoxy]-4-fluorophenyl}imidazo[1,2-a]pyridin-3-yl)methyl]-N-methylcarbamateas an off-white solid (22 mg, 47%). ¹H NMR (400 MHz, DMSO-d₆) 8.60-8.40(br, 2H), 7.61 (s, 1H), 7.57 (d, 1H), 7.32-7.23 (m, 4H), 7.10 (d, 1H),6.82 (td, 1H), 5.76 (s, 1H), 4.77 (s, 2H), 4.12 (t, 2H), 3.65 (s, 3H),3.00 (m, 2H), 2.67 (s, 3H), 1.89 (s, 3H), 1.32 (s, 9H).

Step 2

According to the general method for Boc deprotection (method Btert-butylN-[(6-{2-[2-(3-carbamoyl-1,5-dimethyl-1H-pyrazol-4-yl)ethoxy]-4-fluorophenyl}imidazo[1,2-a]pyridin-3-yl)methyl]-N-methylcarbamate(20 mg, 0.037 mmol) was dissolved in dioxane (2 ml) and treated with asolution of HCl in ether (2M, 3 ml). The solution stirred at roomtemperature for 3 hr and was evaporated under reduced pressure. Thecrude product was dissolved in water and freeze dried to give the titlecompound as a light brown solid (15 mg, 92%). hplc rt 8.9 min LC-MS MH⁺437; ¹H NMR (400 MHz, DMSO-d₆) δ 9.32 (br.s, 2H), 9.08 (s, 1H), 8.27 (s,1H), 7.96 (dd, 2H), 7.63 (dd, 1H), 7.30 (dd, 1H), 7.10 (s, 1H), 6.98(td, 1H), 4.72 (s, 2H), 4.15 (t, 2H), 3.72 (s, 3H), 3.03 (t, 2H), 2.64(t, 3H), 2.06 (s, 3H).

Example 86

4-[2-(5-fluoro-2-{3-[(methylamino)methyl]imidazo[1,2-a]pyridin-6-yl}phenoxy)ethyl]-N,1,5-trimethyl-1H-pyrazole-3-carboxamideStep 1

A solution of4-(2-{2-[3-({[(tert-butoxy)carbonyl](methyl)amino}methyl)imidazo[1,2-a]pyridin-6-yl]-5-fluorophenoxy}ethyl)-1,5-dimethyl-1H-pyrazole-3-carboxylicacid (Example 83 step 2, 55 mg, 0.10 mmol) in DMF (2 mL) was treatedwith triethylamine (0.04 mL, 0.3 mmol), methylamine solution (2M in THF,0.20 mL, 0.20 mmol), hydroxybenztriazole 17.6 mg, 0.13 mmol) and EDCI(24.9 mg, 0.13 mmol). The reaction mixture was stirred at rt for 16 hrs,diluted with DCM and washed with sat. NaHCO₃, water and brine, driedover sodium sulphate and concentrated. The crude product was purified byprep TLC (5% MeOH/DCM) to give tert-butylN-{[6-(2-{2-[1,5-dimethyl-3-(methylcarbamoyl)-1H-pyrazol-4-yl]ethoxy}-4-fluorophenyl)imidazo[1,2-a]pyridin-3-yl]methyl}-N-methylcarbamateas an off-white solid (40 mg, 71%). ¹H NMR (400 MHz, DMSO-d₆) 8.47 (brs, 2H), 7.97 (d, 1H), 7.62 (s, 1H), 7.56 (d, 1H), 7.33 (m, 1H), 7.25 (d,1H), 7.14 (d, 1H), 6.82 (td, 1H), 4.77 (s, 2H), 4.12 (t, 2H), 3.73 (s,3H), 3.00 (m, 2H), 2.70-2.65 (m, 5H), 1.86 (s, 3H), 1.32 (s, 9H).

Step 2

According to the general method for Boc deprotection (method B),tert-butylN-{[6-(2-{2-[1,5-dimethyl-3-(methylcarbamoyl)-1H-pyrazol-4-yl]ethoxy}-4-fluorophenyl)imidazo[1,2-a]pyridin-3-yl]methyl}-N-methylcarbamate(40 mg, 0.073 mmol) was dissolved in dioxane (2 ml) and treated with asolution of HCl in ether (2M, 4 ml). The solution stirred at roomtemperature for 3 hr and was evaporated under reduced pressure. Thecrude product was dissolved in water and freeze-dried to give the titlecompound as a colourless solid (25 mg, 76%). hplc rt 9.2 min LC-MS MH⁺451; ¹H NMR (400 MHz, DMSO-d₆) δ 9.37 (br.s, 2H), 9.09 (s, 1H), 8.27 (s,1H), 7.9-8.0 (m, 3H), 7.65 (dd, 1H), 7.24 (dd, 1H), 6.98 (td, 1H), 4.72(s, 2H), 4.16 (t, 2H), 3.72 (s, 3H), 3.03 (t, 2H), 2.65 (d, 3H), 2.50(t, 2H), 2.06 (s, 3H).

Example 87

4-[2-(5-fluoro-2-{3-[2-(methylamino)ethyl]imidazo[1,2-a]pyridin-6-yl}phenoxy)ethyl]-1,5-dimethyl-1H-pyrazole-3-carboxylicacid Step 1

A solution of tert-butylN-{[6-(4-fluoro-2-hydroxyphenyl)imidazo[1,2-a]pyridin-3-yl]ethyl}-N-methylcarbamate(intermediate 25, 600 mg, 1.3. mmol) in toluene (6.0 mL) was reactedwith methyl 4-(2-hydroxyethyl)-1,5-dimethyl-1H-pyrazole-3-carboxylate(514 mg, 2.6 mmol) and cyanomethylene tributylphosphorane (0.68 mL, 2.6mmol) at 100° C. for 16 hr. The reaction mixture was then diluted withethyl acetate, and washed with water and brine, dried over sodiumsulphate and concentrated. This crude material was purified by prep TLCby elution with DCM:methanol (95:5) to give{[(tert-butoxy)carbonyl](methyl)amino}ethyl)imidazo[1,2-a]pyridin-6-yl]-5-fluorophenoxy}ethyl)-1,5-dimethyl-1H-pyrazole-3-carboxylate(400 mg, 54%). ¹H NMR (400 MHz, DMSO-d₆) δ 8.34 (br. d, 1H), 7.63 (s,1H), 7.53 (d, 1H), 7.50-7.40 (m, 2H), 7.21 (d, 1H), 7.07 (dd, 1H), 6.87(td, 1H), 4.11 (t, 2H), 3.72 (s, 3H), 3.68 (s, 3H), 3.47 (t, 2H), 3.32(s, 3H), 3.11 (t, 2H), 3.00 (t, 2H), 2.73 (s, 3H), 1.92 (s, 3H), 1.33(s, 9H).

Step 2

A solution of{[(tert-butoxy)carbonyl](methyl)amino}ethyl)imidazo[1,2-a]pyridin-6-yl]-5-fluorophenoxy}ethyl)-1,5-dimethyl-1H-pyrazole-3-carboxylate(250 mg, 0.44 mmol) in THF-water (4:1, 3.0 mL) was cooled at 0° C. andtreated with a solution of lithium hydroxide (37 mg, 0.88 mmol) inethanol (0.02 mL) at 0° C. The resulting mixture was stirred at rt for16 hr. The reaction mixture was evaporated under reduced pressure, thecrude reaction mixture was acidified with saturated citric acid solutionand extracted with DCM. The final organic layer was dried over sodiumsulphate and concentrated to afford desired product4-(2-{2-[3-(2-{[(tert-butoxy)carbonyl](methyl)amino}ethyl)imidazo[1,2-a]pyridin-6-yl]-5-fluorophenoxy}ethyl)-1,5-dimethyl-1H-pyrazole-3-carboxylicacid (200 mg, 82%). ¹H NMR (400 MHz, DMSO-d₆) δ 12.4 (br.s, 1H), 8.34(br.d, 1H), 7.66 (s, 1H), 7.54 (d, 1H), 7.45-7.35 (m, 2H), 7.24 (d, 1H),7.13 (dd, 1H), 6.87 (td, 1H), 4.11 (t, 2H), 3.67 (s, 3H), 3.47 (t, 2H),3.32 (s, 3H), 3.11 (t, 2H), 2.99 (t, 2H), 2.77 (s, 3H), 1.94 (s, 3H),1.33 (s, 9H).

Step 3

According to the general method for Boc deprotection (method B)4-(2-{2-[3-(2-{[(tert-butoxy)carbonyl](methyl)amino}ethyl)imidazo[1,2-a]pyridin-6-yl]-5-fluorophenoxy}ethyl)-1,5-dimethyl-1H-pyrazole-3-carboxylicacid (35 mg, 0.06 mmol) was dissolved in dioxane (4 mL) and treated witha solution of HCl in ether (2M, 4 mL). The solution stirred at roomtemperature for 3 hr and was evaporated under reduced pressure. Thecrude product was dissolved in water and freeze dried to give the titlecompound as a light brown solid (27 mg, 87%). hplc rt 3.7 min LC-MS MH⁺452; ¹H NMR (400 MHz, DMSO-d₆) δ 14.6 (br.s, 1H), 8.97 (br. s, 2H), 8.92(s, 1H), 8.15 (s, 1H), 8.00 (dd, 2H), 7.56 (dd, 1H), 7.21 (dd, 1H), 6.97(td, 1H), 4.14 (t, 2H), 3.73 (s, 3H), 3.49 (t, 2H), 3.29 (q, 2H), 3.03(t, 2H), 2.57 (d, 3H), 2.06 (s, 3H).

Example 88

{4-[2-(5-fluoro-2-{3-[2-(methylamino)ethyl]imidazo[1,2-a]pyridin-6-yl}phenoxy)ethyl]-1,5-dimethyl-1H-pyrazol-3-yl}methanolStep 1

A solution of{[(tert-butoxy)carbonyl](methyl)amino}ethyl)imidazo[1,2-a]pyridin-6-yl]-5-fluorophenoxy}ethyl)-1,5-dimethyl-1H-pyrazole-3-carboxylate(Example 87 step 1 intermediate, 100 mg, 0.18 mmol) in THF (3 mL) wascooled at 0° C. and treated with a solution of lithium aluminium hydride(2M in THF, 0.18 ml, 0.09 mmol). The resulting mixture was stirred at 0°C. for 2 hr. the reaction mixture was quenched with sodium sulfatedecahydrate. The reaction mixture was then filtered through Celite bed,which was washed with ethyl acetate. The filtrate was dried over Na₂SO₄and evaporated under reduced pressure. The crude product was purified byprep TLC (5% MeOH/DCM) to tert-butylN-{2-[6-(4-fluoro-2-{2-[3-(hydroxymethyl)-1,5-dimethyl-1H-pyrazol-4-yl]ethoxy}-phenyl)imidazo[1,2-a]pyridin-3-yl]ethyl}-N-methylcarbamateas an off-white solid (50 mg, 53%). ¹H NMR (400′MHz, DMSO-d₆) 8.35(br.d, 1H), 7.50-7.40 (m, 3H), 7.26 (d, 1H), 7.03 (dd, 1H), 6.88 (td,1H), 4.79 (t, 1H), 4.28 (d, 2H), 4.09 (t, 2H), 3.62 (s, 3H), 3.49 (t,2H), 3.14 (t, 2H), 2.79 (s, 3H), 1.94 (s, 3H), 0.98 (s, 9H).

Step 2

According to the general method for Boc deprotection (method B),tert-butylN-{2-[6-(4-fluoro-2-{2-[3-(hydroxymethyl)-1,5-dimethyl-1H-pyrazol-4-yl]ethoxy}-phenyl)imidazo[1,2-a]pyridin-3-yl]ethyl}-N-methylcarbamate(50 mg, 0.04 mmol) was dissolved in dioxane (4 mL) and treated with asolution of HCl in ether (2M, 4 mL). The solution stirred at roomtemperature for 3 hr and was evaporated under reduced pressure. Thecrude product was dissolved in water and freeze-dried to give the titlecompound as a light brown solid (35 mg, 86%). hplc rt 3.6 min LC-MS MH⁺436; ¹H NMR (400 MHz, DMSO-d₆) δ 14.5. (br.s, 1H), 8.91 (m, 3H), 8.13(s, 1H), 7.97 (dd, 2H), 7.52 (dd, 1H), 7.11 (dd, 1H), 6.95 (td, 1H),4.31 (s, 2H), 4.10 (t, 2H), 3.63 (s, 3H), 3.46 (t, 2H), 3.35 (q, 2H),2.78 (t, 2H), 2.54 (d, 3H), 2.00 (s, 3H).

Example 89

4-[2-(5-fluoro-2-{3-[2-(methylamino)ethyl]imidazo[1,2-a]pyridin-6-yl}phenoxy)ethyl]-1,5-dimethyl-1H-pyrazole-3-carboxamideStep 1

A solution of4-(2-{2-[3-({[(tert-butoxy)carbonyl](methyl)amino}methyl)imidazo[1,2-a]pyridin-6-yl]-5-fluorophenoxy}ethyl)-1,5-dimethyl-1H-pyrazole-3-carboxylicacid (Example 87 step 2, 120 mg, 0.22 mmol) in DMF (3 mL) was treatedwith triethylamine (0.09 mL, 0.65 mmol), ammonium chloride (14.0 mg,0.26 mmol), hydroxybenztriazole (37.4 mg, 0.28 mmol) and EDCI (53.0 mg,0.28 mmol). The reaction mixture was stirred at rt for 16 hrs, dilutedwith DCM and washed with sat. NaHCO₃, water and brine, dried over sodiumsulphate and concentrated. The crude product was purified over prep TLC(5% MeOH/DCM) to give tert-butylN-[2-(6-{2-[2-(3-carbamoyl-1,5-dimethyl-1H-pyrazol-4-yl)ethoxy]-4-fluorophenyl}imidazo[1,2-a]pyridin-3-yl)ethyl]-N-methylcarbamateas an off-white solid (70 mg, 58%). ¹H NMR (400 MHz, DMSO-d₆) δ 8.34(br.d, 1H), 7.52 (d, 1H), 7.45-7.30 (m, 2H), 7.26 (d, 1H), 7.20 (dd,1H), 7.10 (s, 1H), 6.86 (td, 1H), 4.14 (t, 2H), 3.68 (s, 3H), 3.49 (t,2H), 3.12 (t, 2H), 3.00 (t, 2H), 2.79 (s, 3H), 1.95 (s, 3H), 0.97 (s,9H).

Step 2

According to the general method for Boc deprotection (method B),tert-butylN-[2-(6-{2-[2-(3-carbamoyl-1,5-dimethyl-1H-pyrazol-4-yl)ethoxy]-4-fluorophenyl}imidazo[1,2-a]pyridin-3-yl)ethyl]-N-methylcarbamate(35 mg, 0.11 mmol) was dissolved in dioxane (2 ml) and treated with asolution of HCl in ether (2M, 4 ml). The solution stirred at roomtemperature for 3 hr and was evaporated under reduced pressure. Thecrude product dissolved in water and freeze dried to give the titlecompound as a light brown solid (25 mg, 87%). hplc rt 4.4 min LC-MS MH⁺451; ¹H NMR (400 MHz, DMSO-d₆) δ 14.7 (br.s, 1H), 9.02 (br. s, 2H), 8.94(s, 1H), 8.15 (s, 1H), 8.03 (dd, 2H), 7.56 (dd, 1H), 7.31-7.28 (m, 2H),7.10 (s, 1H), 6.97 (td, 1H), 4.16 (t, 2H), 3.72 (s, 3H), 3.57 (t, 2H),3.29 (q, 2H), 3.04 (t, 2H), 2.67 (d, 3H), 2.08 (s, 3H).

Example 90

4-[2-(5-fluoro-2-{3-[2-(methylamino)ethyl]imidazo[1,2-a]pyridin-6-yl}phenoxy)ethyl]-N,1,5-trimethyl-1H-pyrazole-3-carboxamideStep 1

A solution of4-(2-{2-[3-({[(tert-butoxy)carbonyl](methyl)amino}methyl)imidazo[1,2-a]pyridin-6-yl]-5-fluorophenoxy}ethyl)-1,5-dimethyl-1H-pyrazole-3-carboxylicacid (Example 87 step 2, 120 mg, 0.22 mmol) in DMF (3 mL) was treatedwith triethylamine (0.09 mL, 0.65 mmol), methylamine solution (2M inTHF, 14.0 mg, 0.26 mmol), hydroxybenztriazole (37.4 mg, 0.28 mmol) andEDCI (53.0 mg, 0.28 mmol). The reaction mixture was stirred at rt for 16hrs, diluted with DCM and washed with sat. NaHCO₃, water and brine,dried over sodium sulphate and concentrated. The crude product waspurified over prep TLC (5% MeOH/DCM) to give tert-butylN-[2-(6-{2-[2-(3-carbamoyl-1,5-dimethyl-1H-pyrazol-4-yl)ethoxy]-4-fluorophenyl}imidazo[1,2-a]pyridin-3-yl)ethyl]-N-methylcarbamateas an off-white solid (70 mg, 58%). ¹H NMR (400 MHz, DMSO-d₆) δ 8.34(br.d, 1H), 7.52 (d, 1H), 7.45-7.30 (m, 2H), 7.26 (d, 1H), 7.20 (dd,1H), 7.10 (s, 1H), 6.86 (td, 1H), 4.14 (t, 2H), 3.68 (s, 3H), 3.49 (t,2H), 3.12 (t, 2H), 3.00 (t, 2H), 2.79 (s, 3H), 1.95 (s, 3H), 0.97 (s,9H).

Step 2

According to the general method for Boc deprotection (method B),tert-butylN-[2-(6-{2-[2-(3-cyano-1,5-dimethyl-1H-pyrazol-4-yl)ethoxy]-4-fluorophenyl}imidazo[1,2-a]pyridin-3-yl)ethyl]-N-methylcarbamate(35 mg, 0.11 mmol) was dissolved in dioxane (2 ml) and treated with asolution of HCl in dioxane (4M, 4 ml). The solution stirred at roomtemperature for 3 hr and was evaporated under reduced pressure. Thecrude product was dissolved in water and freeze dried to give the titlecompound as a light brown solid (15 mg, 52%). hplc rt 5.7 min LC-MS MH⁺465; ¹H NMR (400 MHz, DMSO-d₆) δ 14.5 (br.s, 1H), 8.88 (s, 1H), 8.80(br. s, 2H), 8.08 (s, 1H), 7.99-7.92 (m, 3H), 7.55 (dd, 1H), 7.24 (dd,1H), 6.97 (td, 1H), 4.15 (t, 2H), 3.73 (s, 3H), 3.47 (t, 2H), 3.30 (q,2H), 3.04 (t, 2H), 2.67 (d, 3H), 2.59 (t, 3H), 2.07 (s, 3H).

Example 91

4-[2-(5-fluoro-2-{3-[2-(methylamino)ethyl]imidazo[1,2-a]pyridin-6-yl}phenoxy)ethyl]-1,5-dimethyl-1H-pyrazole-3-carbonitrileStep 1

A solution of tert-butylN-[2-(6-{2-[2-(3-carbamoyl-1,5-dimethyl-1H-pyrazol-4-yl)ethoxy]-4-fluorophenyl}imidazo[1,2-a]pyridin-3-yl)ethyl]-N-methylcarbamate(Example 89 step 1, 40 mg, 0.072 mmol) in THF (1 mL) was treated withtriethylamine (0.048 mL, 0.36 mmol). The reaction mixture was cooled to0° C. before addition of trifluoroacetic anhydride (0.026 mL, 0.17 mmol)and the mixture was then allowed to warm to RT and stirred for 2 hr. Thereaction mixture was quenched with sat NaHCO₃ solution and extractedwith EtOAc, washed with water, brine, dried over sodium sulfate andevaporated under reduced pressure. The crude product was purified overprep TLC (5% MeOH/DCM) to give tert-butylN-[2-(6-{2-[2-(3-cyano-1,5-dimethyl-1H-pyrazol-4-yl)ethoxy]-4-fluorophenyl}imidazo[1,2-a]pyridin-3-yl)ethyl]-N-methylcarbamate(17 mg. 44%). 6 8.31 (br.d, 1H), 7.50-7.35 (m, 3H), 7.16 (d, 1H), 7.09(dd, 1H), 6.90 (td, 1H), 4.17 (t, 2H), 3.71 (s, 3H), 3.47 (t, 2H), 3.10(t, 2H), 2.88 (t, 2H), 2.79 (s, 3H), 1.99 (s, 3H), 0.97 (s, 9H)

Step 2

According to the general method for Boc deprotection (method B),tert-butylN-[2-(6-{2-[2-(3-cyano-1,5-dimethyl-1H-pyrazol-4-yl)ethoxy]-4-fluorophenyl}imidazo[1,2-a]pyridin-3-yl)ethyl]-N-methylcarbamate(17 mg, 0.11 mmol) was dissolved in dioxane (2 ml) and treated with asolution of HCl in ether (2M, 4 ml). The solution stirred at roomtemperature for 3 hr and was evaporated under reduced pressure. Thecrude product was dissolved in water and freeze dried to give the titlecompound as a light brown solid (12 mg, 87%). hplc rt 6.2 min LC-MS MH⁺433; ¹H NMR (400 MHz, DMSO-d₆) δ 14.5 (br.s, 1H) 8.91 (br.s, 2H), 8.86(s, 1H), 8.09 (s, 1H), 7.90 (dd, 2H), 7.51 (dd, 1H), 7.16 (dd, 1H), 6.98(td, 1H), 4.18 (t, 2H), 3.76 (s, 3H), 3.43 (t, 2H), 3.27 (t, 2H), 2.88(q, 2H), 2.67 (t, 3H), 2.14 (s, 3H).

Example 92

4-[2-(5-fluoro-2-{3-[(methylamino)methyl]imidazo[1,2-a]pyridin-6-yl}phenoxy)ethyl]-1,5-dimethyl-1H-pyrazole-3-carbonitrileStep 1

A solution of tert-butylN-[(6-{2-[2-(3-carbamoyl-1,5-dimethyl-1H-pyrazol-4-yl)ethoxy]-4-fluorophenyl}imidazo[1,2-a]pyridin-3-yl)methyl]-N-methylcarbamate(Example 85 step 1, 80 mg, 0.15 mmol) in THF (1.5 mL) was treated withtriethylamine (0.10 mL, 0.75 mmol). The reaction mixture was cooled to0° C. before addition of trifluoroacetic anhydride (0.053 mL, 0.37 mmol)and the mixture was then allowed to warm to RT and stirred for 2 hr. Thereaction mixture was quenched with sat NaHCO₃ solution and extractedwith EtOAc, washed with water, brine, dried over sodium sulfate andevaporated under reduced pressure. The crude product was purified overprep TLC (5% MeOH/DCM) to give tert-butylN-[(6-{2-[2-(3-cyano-1,5-dimethyl-1H-pyrazol-4-yl)ethoxy]-4-fluorophenyl}imidazo[1,2-a]pyridin-3-yl)methyl]-N-methylcarbamate(27 mg. 35%). ¹H NMR (400 MHz, DMSO-d6) δ 8.44 (br.d, 1H), 7.61 (s, 1H),7.52 (d, 1H), 7.33 (dd, 1H), 7.20 (dd, 1H), 7.09 (d, 1H), 6.86 (td, 1H),4.75 (s, 2H), 4.15 (t, 2H), 3.69 (s, 3H), 2.89 (t, 2H), 2.66 (s, 2H),2.79 (s, 3H), 1.93 (s, 3H), 1.32 (s, 9H).

Step 2

According to the general method for Boc deprotection (method B),tert-butylN-[(6-{2-[2-(3-cyano-1,5-dimethyl-1H-pyrazol-4-yl)ethoxy]-4-fluorophenyl}imidazo[1,2-a]pyridin-3-yl)methyl]-N-methylcarbamate(27 mg, 0.11 mmol) was dissolved in dioxane (2 ml) and treated with asolution of HCl in ether (2M, 4 ml). The solution stirred at roomtemperature for 3 hr and was evaporated under reduced pressure. Thecrude product was dissolved in water and freeze dried to give the titlecompound as an off white solid (7 mg, 32%) hplc rt 5.2 min LC-MS MH⁺419; ¹H NMR (400 MHz, DMSO-d₆) δ 9.40 (br.s, 2H), 9.06 (s, 1H), 8.29 (s,1H), 7.89 (dd, 2H), 7.61 (dd, 1H), 7.16 (dd, 1H), 6.98 (td, 1H), 4.69(br.s, 2H), 4.18 (t, 2H), 3.74 (s, 3H), 2.88 (t, 2H), 2.61 (t, 2H), 2.13(s, 3H).

Example 93

4-(2-{2-[3-(2-aminoethyl)imidazo[1,2-a]pyridin-6-yl]-5-fluorophenoxy}ethyl)-1,5-dimethyl-1H-pyrazole-3-carboxylicacid Step 1

A solution of tert-butylN-{[6-(4-fluoro-2-hydroxyphenyl)imidazo[1,2-a]pyridin-3-yl]ethyl}-carbamate(intermediate 23, 600 mg, 1.6 mmol) in toluene (10 mL) was reacted withmethyl 4-(2-hydroxyethyl)-1,5-dimethyl-1H-pyrazole-3-carboxylate (640mg, 3.2 mmol) and cyanomethylene tributylphosphorane (0.85 mL, 3.2 mmol)at 100° C. for 16 hr. The reaction mixture was then diluted with ethylacetate, and washed with water and brine, dried over sodium sulphate andconcentrated. This crude material was purified by column chromatographyby elution with DCM:methanol (95:5) to give{[2-(tert-butoxy)carbonyl]amino}ethyl)imidazo[1,2-a]pyridin-6-yl]-5-fluorophenoxy}ethyl)-1,5-dimethyl-1H-pyrazole-3-carboxylate(500 mg, 56%). ¹H NMR (400 MHz, CDCl₃) δ 8.06 (s, 1H), 7.58 (d, 1H),7.50 (s, 1H), 7.27 (td, 1H), 7.20 (d, 1H), 6.78 (dd, 1H), 6.73 (td, 1H),4.88 (s, 1H), 4.18 (t, 2H), 3.90 (s, 3H), 3.73 (s, 3H), 3.52 (t, 2H),3.09 (t, 2H), 1.84 (s, 3H), 1.34 (s, 9H).

Step 2

A solution of(2-{(tert-butoxy)carbonyl]amino}ethyl)imidazo[1,2-a]pyridin-6-yl]-5-fluorophenoxy}ethyl)-1,5-dimethyl-1H-pyrazole-3-carboxylate(300 mg, 0.54 mmol) in THF-water (4:1, 3.0 mL) was cooled at 0° C. andtreated with a solution of lithium hydroxide (46 mg, 1.09 mmol) inethanol (0.02 mL) at 0° C. The resulting mixture was stirred at rt for16 hr. The reaction mixture was evaporated under reduced pressure, thecrude reaction mixture was acidified with saturated citric acid solutionand extracted with DCM. The final organic layer was dried over sodiumsulphate and concentrated to afford desired product4-(2-{2-[3-(2-{(tert-butoxy)carbonyl]amino}ethyl)imidazo[1,2-a]pyridin-6-yl]-5-fluorophenoxy}ethyl)-1,5-dimethyl-1H-pyrazole-3-carboxylicacid (280 mg, 96%) as a brown solid. ¹H NMR (400 MHz, CDCl₃) δ 8.07 (s,1H), 7.73 (d, 1H), 7.48 (s, 1H), 7.29 (m, 1H), 6.80-6.70 (m, 1H), 4.73(s, 1H), 4.14 (t, 2H), 3.71 (s, 3H), 3.49 (t, 2H), 3.09 (s, 3H), 1.96(s, 3H), 1.40 (d, 9H).

Step 3

According to the general method for Boc deprotection (method B)4-(2-{2-[3-(2-{2-[(tert-butoxy)carbonyl]amino}ethyl)imidazo[1,2-a]pyridin-6-yl]-5-fluorophenoxy}ethyl)-1,5-dimethyl-1H-pyrazole-3-carboxylicacid (40 mg, 0.06 mmol) was dissolved in dioxane (4 mL) and treated witha solution of HCl in ether (2M, 4 mL). The solution stirred at roomtemperature for 3 hr and was evaporated under reduced pressure. Thecrude product was dissolved in water and freeze dried to give the titlecompound as a light brown solid (30 mg, 92%). hplc rt 3.7 min LC-MS MH⁺452; ¹H NMR (400 MHz, DMSO-d₆) δ 14.6 (br.s, 1H), 12.4 (br.s, 1H), 8.90(s, 1H), 8.14 (s, 3H), 8.00 (dd, 2H), 7.55 (dd, 1H), 7.21 (dd, 1H), 6.97(td, 1H), 4.14 (t, 2H), 3.74 (s, 3H), 3.43 (t, 2H), 3.20 (q, 2H), 3.03(t, 2H), 2.06 (s, 3H).

Example 94

4-(2-{2-[3-(2-aminoethyl)imidazo[1,2-a]pyridin-6-yl]-5-fluorophenoxy}ethyl)-N,1,5-trimethyl-1H-pyrazole-3-carboxamideStep 1

A solution of4-(2-{2-[3-({[(tert-butoxy)carbonyl](methyl)amino}methyl)imidazo[1,2-a]pyridin-6-yl]-5-fluorophenoxy}ethyl)-1,5-dimethyl-1H-pyrazole-3-carboxylicacid (Example 93 step 2, 100 mg, 0.19 mmol) in THF (2 mL) was treatedwith triethylamine (0.078 mL, 0.56 mmol), methylamine solution (2M inTHF, 1.8 mL, 0.26 mmol), hydroxybenztriazole (31.9 mg, 0.24 mmol) andEDCI (45.3 mg, 0.24 mmol). The reaction mixture was stirred at rt for 16hrs, diluted with DCM and washed with sat. NaHCO₃, water and brine,dried over sodium sulphate and concentrated. The crude product waspurified by prep TLC (5% MeOH/DCM) to give tert-butylN-[2-(6-{2-[2-(3-(methyl)carbamoyl-1,5-dimethyl-1H-pyrazol-4-yl)ethoxy]-4-fluorophenyl}imidazo[1,2-a]pyridin-3-yl)ethyl]-carbamateas an off-white solid (60 mg, 58%). ¹H NMR (400 MHz, CDCl₃) δ 8.07 (s,1H), 7.54 (d, 1H), 7.46 (s, 1H), 7.19 (m, 1H), 6.85 (td, 1H), 6.77 (dd,1H), 6.70 (td, 1H), 5.03 (s, 1H), 4.22 (t, 2H), 3.62 (s, 3H), 3.48 (t,2H), 3.09 (s, 3H), 2.92 (s, 3H), 1.80 (s, 3H), 1.39 (d, 9H).

Step 2

According to the general method for Boc deprotection (method B)tert-butyl N-[2-(6-{2-[2-(3-(methyl)carbamoyl-1,5-dimethyl-1H-pyrazol-4-yl)ethoxy]-4-fluorophenyl}imidazo[1,2-a]pyridin-3-yl)ethyl]-carbamate(40 mg, 0.073 mmol) was dissolved in dioxane (2 ml) and treated with asolution of HCl in ether (2M, 5 ml). The solution stirred at roomtemperature for 3 hr and was evaporated under reduced pressure. Thecrude product dissolved in water and freeze dried to give the titlecompound as a light brown solid (30 mg, 92%) hplc rt 7.6 min LC-MS MH⁺451; ¹H NMR (400 MHz, DMSO-d₆) δ 14.7 (br.s, 1H), 8.95 (s, 1H), 8.19(br. s, 3H), 8.15 (s, 1H), 8.02 (dd, 2H), 7.91 (q, 1H), 7.56 (dd, 1H),7.24 (dd, 1H), 6.97 (td, 1H), 4.16 (t, 2H), 3.73 (s, 3H), 3.45 (t, 2H),3.20 (q, 2H), 3.04 (t, 2H), 2.67 (d, 3H), 2.07 (s, 3H).

Example 95

[4-(2-(2-[3-(2-aminoethyl)imidazo[1,2-a]pyridin-6-yl]-5-fluorophenoxy}ethyl)-1,5-dimethyl-1H-pyrazol-3-yl]methanolStep 1

A solution of {[(tert-butoxy)carbonyl]amino}ethyl)imidazo[1,2-a]pyridin-6-yl]-5-fluorophenoxy}ethyl)-1,5-dimethyl-1H-pyrazole-3-carboxylate(Example 93 step 1 intermediate, 100 mg, 0.18 mmol) in THF (3 mL) wascooled at 0° C. and treated with a solution of lithium aluminium hydride(2M in THF, 0.18 ml, 0.09 mmol). The resulting mixture was stirred at 0°C. for 2 hr. the reaction mixture was quenched with sodium sulfatedecahydrate. The reaction mixture was then filtered through Celite bed,which was washed with ethyl acetate. The filtrate was dried over Na₂SO₄and evaporated under reduced pressure. The crude product was purified byprep TLC (5% MeOH/DCM) to tert-butylN-{2-[6-(4-fluoro-2-{2-[3-(hydroxymethyl)-1,5-dimethyl-1H-pyrazol-4-yl]ethoxy}-phenyl)-imidazo[1,2-a]pyridin-3-yl]ethyl}-carbamate(60 mg, 63%). ¹H NMR (400 MHz, CDCl₃) δ 8.05 (s, 1H), 7.58 (d, 1H), 7.46(s, 1H), 7.20 (m, 1H), 6.75-6.70 (m, 2H), 4.99 (s, 1H), 4.47 (s, 2H),4.05 (t, 2H), 3.60 (s, 3H), 3.48 (t, 2H), 3.06 (t, 3H), 2.84 (t, 2H),1.92 (s, 3H), 1.36 (d, 9H).

Step 2

According to the general method for Boc deprotection (method B),tert-butylN-{2-[6-(4-fluoro-2-{2-[3-(hydroxymethyl)-1,5-dimethyl-1H-pyrazol-4-yl]ethoxy}-phenyl)imidazo[1,2-a]pyridin-3-yl]ethyl}-carbamate(60 mg, 0.0115 mmol) was dissolved in dioxane (4 mL) and treated with asolution of HCl in ether (2M, 3 mL). The solution stirred at roomtemperature for 3 hr and was evaporated under reduced pressure. Thecrude product was dissolved in water and freeze-dried to give the titlecompound as a light brown solid (40 mg, 82%). hplc rt 7.2 min LC-MS MH⁺424; ¹H NMR (400 MHz, DMSO-d₆) δ 14.6 (br.s, 1H), 8.94 (s, 1H), 8.14(br. s, 3H), 8.03 (dd, 2H), 7.56 (dd, 1H), 7.13 (dd, 1H), 6.97 (td, 1H),4.26 (s, 2H), 4.14 (t, 2H), 3.62 (s, 3H), 3.43 (t, 2H), 3.20 (q, 2H),2.80 (t, 2H), 2.03 (s, 3H).

Example 96

4-(2-{2-[3-(2-aminoethyl)imidazo[1,2-a]pyridin-6-yl]-5-fluorophenoxy}ethyl)-1,5-dimethyl-1H-pyrazole-3-carboxamideStep 1

A solution of4-(2-{2-[3-(2-{[(tert-butoxy)carbonyl]amino}ethyl)imidazo[1,2-a]pyridin-6-yl]-5-fluorophenoxy}ethyl)-1,5-dimethyl-1H-pyrazole-3-carboxylicacid (Example 93 step 2, 180 mg, 0.34 mmol) in DMF (3 mL) was treatedwith triethylamine (0.14 mL, 1.0 mmol), ammonium chloride (21.5 mg, 0.40mmol), hydroxybenztriazole (57.3 mg, 0.43 mmol) and EDCI (81.5 mg, 0.43mmol). The reaction mixture was stirred at rt for 16 hrs, diluted withDCM and washed with sat. NaHCO₃, water and brine, dried over sodiumsulphate and concentrated. The crude product was purified by prep TLC(5% MeOH/DCM) to give tert-butylN-[2-(6-{2-[2-(3-carbamoyl-1,5-dimethyl-1H-pyrazol-4-yl)ethoxy]-4-fluorophenyl}imidazo[1,2-a]pyridin-3-yl)ethyl]carbamateas a light brown solid (120 mg, 67%). ¹H NMR (400 MHz, CDCl₃) δ 8.10 (s,1H), 7.55 (d, 1H), 7.46 (s, 1H), 7.20 (m, 1H), 6.79 (dd, 1H), 6.75-6.70(m, 2H), 5.28 (s, 1H), 5.25 (s, 1H), 4.17 (t, 2H), 3.65 (s, 3H), 3.48(t, 2H), 3.08 (t, 3H), 1.87 (s, 3H), 1.40 (d, 9H).

Step 2

According to the general method for Boc deprotection (method B),tert-butylN-[2-(6-{2-[2-(3-carbamoyl-1,5-dimethyl-1H-pyrazol-4-yl)ethoxy]-4-fluorophenyl}imidazo[1,2-a]pyridin-3-yl)ethyl]carbamate(50 mg, 0.093 mmol) was dissolved in dioxane (2 ml) and treated with asolution of HCl in ether (2M, 4 ml). The solution stirred at roomtemperature for 3 hr and was evaporated under reduced pressure. Thecrude product dissolved in water and freeze dried to give the titlecompound as a light brown solid (30 mg, 74%). hplc rt 4.8 min LC-MS MH⁺437; ¹H NMR (400 MHz, DMSO-d₆) δ 14.8 (br.s, 1H), 8.94 (s, 1H), 8.23(br. s, 3H), 8.15 (s, 1H), 8.03 (dd, 2H), 7.56 (dd, 1H), 7.30 (dd, 2H),7.10 (s, 1H), 6.97 (td, 1H), 4.16 (t, 2H), 3.71 (s, 3H), 3.46 (t, 2H),3.20 (q, 2H), 3.04 (t, 2H), 2.07 (s, 3H).

Example 97

2-[6-(2-{2-[3-(aminomethyl)-1,5-dimethyl-1H-pyrazol-4-yl]ethoxy}-4-fluorophenyl)imidazo[1,2-a]pyridin-3-yl]ethan-1-amineStep 1

A solution of tert-butylN-{2-[6-(4-fluoro-2-{2-[3-(hydroxymethyl)-1,5-dimethyl-1H-pyrazol-4-yl]ethoxy}-phenyl)imidazo[1,2-a]pyridin-3-yl]ethyl}-carbamate(Example 95 Step 170 mg, 0.13 mmol) in DCM (3 mL) was cooled at 0° C.and treated with trimethylamine (0.056 mL, 0.20 mmol) and mesylchloride(0.016 mL, 0.20 mmol), both added drop wise. The reaction mixture wasstirred at rt for 2 hr, diluted with DCM washed with sat. NaHCO₃solution and brine, dried over sodium sulphate and concentrated. Thecrude tert-butylN-(2-{6-[4-fluoro-2-(2-{3-[(methanesulfonyloxy)methyl]-1,5-dimethyl-1H-pyrazol-4-yl}ethoxy)phenyl]-imidazo[1,2-a]pyridin-3-yl}ethyl)carbamate(70 mg, 87%) was taken onto the next step with any purification.

Step 2

A solution of tert-butylN-(2-{6-[4-fluoro-2-(2-{3-[(methanesulfonyloxy)methyl]-1,5-dimethyl-1H-pyrazol-4-yl}ethoxy)phenyl]-imidazo[1,2-a]pyridin-3-yl}ethyl)carbamate(70 mg, 0.116 mmol) in DMF (2 mL) was treated with sodium azide (13.7mg, 0.23 mmol). The reaction mixture was heated at 90° C. for 16 hrs,diluted with DCM, washed with sat. NaHCO₃ solution and brine, dried oversodium sulphate and concentrated. The crude product, tert-butylN-{2-[6-(2-{2-[3-(azidomethyl)-1,5-dimethyl-1H-pyrazol-4-yl]ethoxy}-4-fluorophenyl)imidazo[1,2-a]pyridin-3-yl]ethyl}carbamate(50 mg, 80%) was taken onto the next step without further purification.

Step 3

A solution of tert-butylN-{2-[6-(2-{2-[3-(azidomethyl)-1,5-dimethyl-1H-pyrazol-4-yl]ethoxy}-4-fluorophenyl)imidazo[1,2-a]pyridin-3-yl]ethyl}carbamatein MeOH (1.5 mL) was degassed with argon for about 10 min followed bythe addition of Pd/C (15 mg) and the resultant mixture was stirred underH₂ (balloon pressure) for 2 h at ambient temperature. Reaction mixturewas filtered through Celite bed, washed with MeOH and the filtrate wasevaporated. The crude product was purified over prep TLC (5% MeOH/DCM)to give tert-butylN-{2-[6-(2-{2-[3-(aminomethyl)-1,5-dimethyl-1H-pyrazol-4-yl]ethoxy}-4-fluorophenyl)imidazo[1,2-a]pyridin-3-yl]ethyl}carbamate(17 mg, 36%) as an off-white solid, ¹H NMR (400 MHz, DMSO-d₆) δ 8.37(br. s, 4H), 7.52 (td, 1H), 7.45-7.40 (m, 2H), 7.26 (d, 1H), 7.06 (d,1H), 7.00 (dd, 2H), 6.89 (td, 1H), 4.08 (t, 2H), 3.56 (s, 3H), 3.52 (s,2H), 3.29 (t, 2H), 3.02 (t, 2H), 2.77 (t, 2H), 1.92 (s, 3H), 1.33 (s,9H).

Step 4

According to the general method for Boc deprotection (method B),tert-butylN-{2-[6-(2-{2-[3-(aminomethyl)-1,5-dimethyl-1H-pyrazol-4-yl]ethoxy}-4-fluorophenyl)imidazo[1,2-a]pyridin-3-yl]ethyl}carbamate(17 mg, 0.033 mmol) was dissolved in dioxane (2 ml), cooled at 0° C.,and treated with a solution of HCl in ether (2M, 3 ml). The solutionstirred at room temperature for 3 hr and was evaporated under reducedpressure. The crude product dissolved in water and freeze dried to givethe title compound as a light brown solid (8 mg, 58%). hplc rt 4.5 minLC-MS MH⁺ 423; ¹H NMR (400 MHz, DMSO-d₆) δ 14.7 (br.s, 1H), 9.00 (s,1H), 8.24 (br. s, 4H), 8.15 (s, 1H), 8.11 (d, 1H), 8.01 (d, 2H), 7.57(td, 1H), 7.13 (dd, 2H), 6.98 (td, 1H), 4.10 (t, 2H), 3.67 (s, 3H), 3.46(t, 2H), 3.20 (t, 2H), 2.82 (t, 2H), 2.05 (s, 3H).

Example 98

N-{[4-(2-{2-[3-(2-aminoethyl)imidazo[1,2-a]pyridin-6-yl]-5-fluorophenoxy}ethyl)-1,5-dimethyl-1H-pyrazol-3-yl]methyl}acetamideStep 1

A solution of tert-butylN-{2-[6-(2-{2-[3-(aminomethyl)-1,5-dimethyl-1H-pyrazol-4-yl]ethoxy}-4-fluorophenyl)imidazo[1,2-a]pyridin-3-yl]ethyl}carbamate(Example 97 Step 3, 90 mg, 0.17 mmol) in DCM (3 mL) was cooled at 0° C.before dropwise addition of triethylamine (0.048 mL, 0.344 mmol)followed by acetyl chloride (0.018 mL, 0.258 mmol). The reaction mixturewas warmed to rt for 2 hr, diluted with DCM washed with sat.NaHCO₃solution and brine, dried over sodium sulphate and concentrated underreduced pressure. The crude product was purified by prep TLC (5%MeOH/DCM) to give tert-butylN-{2-[6-(2-{2-[3-(acetamidomethyl)-1,5-dimethyl-1H-pyrazol-4-yl]ethoxy}-4-fluorophenyl)imidazo[1,2-a]pyridin-3-yl]ethyl}carbamate(40 mg, 41%). ¹H NMR (400 MHz, DMSO-d₆) δ 8.38 (s, 1H), 8.04 (t, 1H),7.52 (d, 1H), 7.50-7.40 (m, 2H), 7.30 (d, 1H), 7.05-6.95 (m, 2H), 6.88(td, 1H), 4.07 (d, 2H), 4.01 (t, 2H), 3.57 (s, 3H), 3.09 (m, 2H), 3.04(t, 2H), 2.75 (t, 2H), 1.91 (s, 3H), 1.74 (s, 3H), 1.33 (s, 9H).

Step 2

According to the general method for Boc deprotection (method B),tert-butylN-{2-[6-(2-{2-[3-(acetamidomethyl)-1,5-dimethyl-1H-pyrazol-4-yl]ethoxy}-4-fluorophenyl)imidazo[1,2-a]pyridin-3-yl]ethyl}carbamate(40 mg, 0.07 mmol) was dissolved in dioxane (2 mL), cooled to 0° C. andtreated with a solution of HCl in ether (2M, 5 mL). The solution stirredat room temperature for 3 hr and was evaporated under reduced pressure.The crude product dissolved in water and freeze dried to give the titlecompound as a light brown solid (30 mg, 91%). hplc rt 5.3 min LC-MS MH⁺465; ¹H NMR (400 MHz, DMSO-d₆) δ 14.6 (br.s, 1H), 8.95 (s, 1H),8.17-8.08 (m, 5H), 7.99 (d, 1H), 7.55 (td, 1H), 7.09 (dd, 1H), 6.96 (td,1H), 4.05 (t, 2H), 3.95 (d, 2H), 3.62 (s, 3H), 3.45 (t, 2H), 3.20 (q,2H), 2.76 (t, 2H), 2.05 (s, 3H), 1.72 (s, 3H).

Example 99

N-{[4-(2-{2-[3-(2-aminoethyl)imidazo[1,2-a]pyridin-6-yl]-5-fluorophenoxy}ethyl)-1,5-dimethyl-1H-pyrazol-3-yl]methyl}methanesulfonamideStep 1

A solution of tert-butylN-{2-[6-(2-{2-[3-(aminomethyl)-1,5-dimethyl-1H-pyrazol-4-yl]ethoxy}-4-fluorophenyl)imidazo[1,2-a]pyridin-3-yl]ethyl}carbamate(Example 97 Step 3, 90 mg, 0.17 mmol) in DCM (3 mL) was cooled at 0° C.before dropwise addition of triethylamine (0.048 mL, 0.344 mmol)followed by mesyl chloride (0.02 mL, 0.258 mmol). The reaction mixturewas warmed to rt for 2 hr, diluted with DCM washed with sat.NaHCO₃solution and brine, dried over sodium sulphate and concentrated underreduced pressure. The crude product was purified by prep TLC (5%MeOH/DCM) to give tert-butylN-{2-[6-(4-fluoro-2-{2-[3-(methanesulfonamidomethyl)-1,5-dimethyl-1H-pyrazol-4-yl]ethoxy}phenyl)imidazo[1,2-a]pyridin-3-yl]ethyl}carbamate(30 mg, 29%). ¹H NMR (400 MHz, DMSO-d₆) δ 8.36 (s, 1H), 7.51 (d, 1H),7.50-7.40 (m, 2H), 7.29 (d, 1H), 7.20 (t, 1H), 7.05-6.95 (m, 2H), 6.89(td, 1H), 4.08 (t, 2H), 3.95 (d, 2H), 3.58 (s, 3H), 3.28 (m, 2H), 3.09(t, 2H), 3.04 (t, 2H), 2.81 (m, 5H), 1.91 (s, 3H), 1.33 (s, 9H).

Step 2

According to the general method for Boc deprotection (method Btert-butylN-{2-[6-(4-fluoro-2-{2-[3-(methanesulfonamidomethyl)-1,5-dimethyl-1H-pyrazol-4-yl]ethoxy}phenyl)imidazo[1,2-a]pyridin-3-yl]ethyl}carbamate(30 mg, 0.05 mmol) was dissolved in dioxane (2 ml) cooled at 0° C. andtreated with a solution of HCl in ether (2M, 4 ml). The solution stirredat room temperature for 3 hr and was evaporated under reduced pressure.The crude product dissolved in water and freeze dried to give the titlecompound as a light brown solid (19 mg, 76%). hplc rt 5.5 min LC-MS MH⁺501; ¹H NMR (400 MHz, DMSO-d₆) δ 14.6 (br.s, 1H), 8.90 (s, 1H), 8.05(br. s, 4H), 8.04 (d, 1H), 7.95 (d, 1H), 7.56 (dd, 1H), 7.19 (t, 1H),7.07 (dd, 1H), 6.94 (td, 1H), 4.08 (t, 2H), 3.90 (d, 2H), 3.60 (s, 3H),3.41 (t, 2H), 3.17 (q, 2H), 2.81 (s, 3H), 2.78 (t, 2H), 2.01 (s, 3H).

Example 100

2-[6-(4-fluoro-2-{2-[3-(methoxymethyl)-1,5-dimethyl-1H-pyrazol-4-yl]ethoxy}phenyl)imidazo[1,2-a]pyridin-3-yl]ethan-1-amineStep 1

A solution of tert-butylN-{2-[6-(4-fluoro-2-{2-[3-(hydroxymethyl)-1,5-dimethyl-1H-pyrazol-4-yl]ethoxy}-phenyl)imidazo[1,2-a]pyridin-3-yl]ethyl}-carbamate(Example 95 Step 1, 200 mg, 0.36 mmol) in DCM (5 mL) was cooled at 0° C.and treated with triethylamine (0.152 mL, 1.09 mmol) followed bydropwise addition of mesyl chloride (0.042 mL, 0.544 mmol). The reactionmixture was stirred at rt for 2 hr, diluted with DCM, washed withsat.NaHCO₃ solution and brine, dried over sodium sulphate andconcentrated under reduced pressure. Crude LCMS showed formation ofcorresponding —Cl derivative tert-butylN-{2-[6-(4-fluoro-2-{2-[3-chloro-1,5-dimethyl-1H-pyrazol-4-yl]ethoxy}phenyl)imidazo[1,2-a]pyridin-3-yl]ethyl}carbamate(196 mg, 100%. The crude was forwarded to next step without anypurification.

Step 2

A solution of tert-butylN-{2-[6-(4-fluoro-2-{2-[3-chloro-1,5-dimethyl-1H-pyrazol-4-yl]ethoxy}phenyl)imidazo[1,2-a]pyridin-3-yl]ethyl}carbamate(100 mg, 0.18 mmol) in methanol (1.0 mL) was treated with sodiummethoxide (54 mg, 0.92 mmol) The reaction mixture was stirred at rt for16 hrs, diluted with EtOAc, washed with water and brine, dried oversodium sulphate and concentrated under reduced pressure. The crudeproduct was purified by prep TLC to give tert-butylN-{2-[6-(4-fluoro-2-{2-[3-(methoxymethyl)-1,5-dimethyl-1H-pyrazol-4-yl]ethoxy}phenyl)imidazo[1,2-a]pyridin-3-yl]ethyl}carbamate(20 mg, 20%). The product was taken onto the next step without fullcharacterisation

Step 3

According to the general method for Boc deprotection (method B),tert-butylN-{2-[6-(4-fluoro-2-{2-[3-(methoxymethyl)-1,5-dimethyl-1H-pyrazol-4-yl]ethoxy}phenyl)imidazo[1,2-a]pyridin-3-yl]ethyl}carbamate(20 mg, 0.1037 mmol) was dissolved in dioxane (2 ml) and treated with asolution of HCl in ether (2M, 2 ml). The solution stirred at roomtemperature for 3 hr and was evaporated under reduced pressure. Thecrude product dissolved in water and freeze dried to give the titlecompound as a light brown solid (14 mg, 86%). hplc rt 8.3 min LC-MS MH⁺438; ¹H NMR (400 MHz, DMSO-d₆) δ 14.6 (br.s, 1H), 8.93 (s, 1H), 8.23(br. s, 3H), 8.20-8.10 (m, 4H), 8.00 (dd, 2H), 7.56 (dd, 1H), 7.11 (dd,2H), 6.97 (td, 1H), 4.16 (s, 2H), 4.10 (t, 2H), 3.63 (s, 3H), 3.43 (t,2H), 3.19 (q, 2H), 3.13 (s, 3H), 2.77 (t, 2H), 2.03 (s, 3H).

Example 101

2-[6-(4-fluoro-2-{2-[3-(methanesulfonylmethyl)-1,5-dimethyl-1H-pyrazol-4-yl]ethoxy}phenyl)imidazo[1,2-a]pyridin-3-yl]ethan-1-amineStep 1

A solution of tert-butylN-{2-[6-(4-fluoro-2-{2-[3-chloro-1,5-dimethyl-1H-pyrazol-4-yl]ethoxy}phenyl)imidazo[1,2-a]pyridin-3-yl]ethyl}carbamate(Example 100 Step 1, 100 mg, 0.18 mmol) in DMF (1.5 mL) was treated withNaSO₂Me (37.7 mg, 0.37 mmol) and the reaction mixture was stirred at RTfor 6 h. The reaction mixture was diluted with EtOAc and washed withwater. Organic layer was dried over Na₂SO⁴ and concentrated underreduced pressure. The crude product was purified by prep TLC (5% MeOH inDCM) to afford desired product tert-butylN-{2-[6-(4-fluoro-2-{2-[3-(methanesulfonylmethyl)-1,5-dimethyl-1H-pyrazol-4-yl]ethoxy}phenyl)imidazo[1,2-a]pyridin-3-yl]ethyl}carbamate(17 mg, 16%), which was taken onto the next step without fullcharacterisation.

Step 2

According to the general method for Boc deprotection (method B),tert-butylN-{2-[6-(4-fluoro-2-{2-[3-(methanesulfonylmethyl)-1,5-dimethyl-1H-pyrazol-4-yl]ethoxy}phenyl)imidazo[1,2-a]pyridin-3-yl]ethyl}carbamate(17 mg, 0.029 mmol) treated with a solution of HCl in ether (2M, 2 ml).The solution stirred at room temperature for 4 hr and was evaporatedunder reduced pressure. The crude product was triturates with ether togive a yellow solid, which was dissolved in water and freeze dried togive the title compound (15 mg, 93%). hplc rt 7.6 min LC-MS MH⁺ 486; ¹HNMR (400 MHz, DMSO-d₆) δ 14.6 (br.s, 1H), 8.96 (s, 1H), 8.14 (br. s,4H), 8.09 (d, H), 7.99 (d, 2H), 7.55 (dd, 1H), 7.09 (dd, 2H), 6.97 (td,1H), 4.27 (s, 2H), 4.12 (t, 2H), 3.67 (s, 3H), 3.44 (t, 2H), 3.19 (q,2H), 2.91 (s, 3H), 2.84 (t, 2H), 2.07 (s, 3H).

Example 102

{[6-(4-fluoro-2-{2-[3-(methanesulfonylmethyl)-1,5-dimethyl-1H-pyrazol-4-yl]ethoxy}phenyl)imidazo[1,2-a]pyridin-3-yl]methyl}(methyl)amineStep 1

A solution of tert-butylN-{[6-(4-fluoro-2-{2-[3-(hydroxymethyl)-1,5-dimethyl-1H-pyrazol-4-yl]ethoxy}-phenyl)imidazo[1,2-a]pyridin-3-yl]methyl}-N-methylcarbamate(Example 84 Step 1, 750 mg, 1.4 mmol) in DCM (1 mL) was cooled at 0° C.and treated with triethylamine (0.4 mL, 2.8 mmol) followed by dropwiseaddition of mesyl chloride (0.17 mL, 2.15 mmol). The reaction mixturewas stirred at rt for 2 hr, diluted with DCM, washed with sat. NaHCO₃solution and brine, dried over sodium sulphate and concentrated underreduced pressure to give tert-butylN-({6-[4-fluoro-2-(2-{3-[(methanesulfonyloxy)methyl]-1,5-dimethyl-1H-pyrazol-4-yl}ethoxy)phenyl]imidazo[1,2-a]pyridin-3-yl}methyl)-N-methylcarbamate(700 mg, 81%.) ¹H NMR (400 MHz, CDCl₃) δ 8.96 (s, 1H), 8.33 (d, 1H),7.93 (d, 1H), 7.81 (s, 1H) 7.29 (td, 1H), 6.74 (m, 2H), 4.80 (s, 2H),4.51 (s, 2H), 4.11 (t, 2H), 3.78 (s, 3H), 2.93 (t, 2H), 2.67 (s, 3H),2.82 (s, 3H), 2.10 (s, 3H), 1.41 (s, 9H).

Step 2

A solution of tert-butylN-({6-[4-fluoro-2-(2-{3-[(methanesulfonyloxy)methyl]-1,5-dimethyl-1H-pyrazol-4-yl}ethoxy)phenyl]imidazo[1,2-a]pyridin-3-yl}methyl)-N-methylcarbamate(150 mg, 0.28 mmol) in DMF (1.5 mL) was treated with NaSO2Me (56.5 mg,0.55 mmol) and the reaction mixture was stirred at RT for 16 h, then at80° C. for 3 hr. The reaction mixture was diluted with EtOAc and washedwith water. The organic layer was dried over Na₂SO₄ and concentratedunder reduced pressure. The crude product was purified by prep TLC (5%MeOH in EtOAc) to afford desired product tert-butylN-{[6-(4-fluoro-2-{2-[3-(methanesulfonylmethyl)-1,5-dimethyl-1H-pyrazol-4-yl]ethoxy}phenyl)imidazo[1,2-a]pyridin-3-yl]methyl}-N-methylcarbamate(23 mg, 14%), which was taken onto the next step without fullcharacterisation.

Step 3

According to the general method for Boc deprotection (method B),tert-butylN-{[6-(4-fluoro-2-{2-[3-(methanesulfonylmethyl)-1,5-dimethyl-1H-pyrazol-4-yl]ethoxy}phenyl)imidazo[1,2-a]pyridin-3-yl]methyl}-N-methylcarbamate(23 mg, 0.039 mmol) treated with a solution of HCl in ether (2M, 3 mL).The solution stirred at room temperature for 4 hr and was evaporatedunder reduced pressure. The crude product was triturated with ether togive a yellow solid, which was dissolved in water and freeze dried togive the title compound (18 mg, 94%). hplc rt 4.7 min LC-MS MH⁺ 486; ¹HNMR (400 MHz, DMSO-d₆) δ 9.71 (s, 2H), 9.20 (s, 1H), 8.40 (s, 1H), 8.15(d, 1H), 7.99 (d, 1H), 7.73 (td, 1H), 7.10 (dd, 2H), 6.99 (td, 1H), 4.74(s, 2H), 4.25 (s, 2H), 4.13 (t, 2H), 3.67 (s, 3H), 2.91 (s, 3H), 2.84(t, 2H), 2.64 (s, 3H), 2.06 (s, 3H).

Example 103

{[6-(4-fluoro-2-{2-[3-(methoxymethyl)-1,5-dimethyl-1H-pyrazol-4-yl]ethoxy}phenyl)imidazo[1,2-a]pyridin-3-yl]methyl}(methyl)amineStep 1

A solution tert-butylN-({6-[4-fluoro-2-(2-{3-[(methanesulfonyloxy)methyl]-1,5-dimethyl-1H-pyrazol-4-yl}ethoxy)phenyl]imidazo[1,2-a]pyridin-3-yl}methyl)-N-methylcarbamate(Example 102, Step 1, 150 mg, 0.28 mmol) in methanol (1.0 mL) wastreated with sodium methoxide (5M, 0.3 mL, 1.34 mmol) The reactionmixture was stirred at rt for 16 hrs, diluted with EtOAc, washed withwater and brine, dried over sodium sulphate and concentrated underreduced pressure. The crude product was purified by prep TLC to givetert-butylN-{[6-(4-fluoro-2-{2-[3-(methoxymethyl)-1,5-dimethyl-1H-pyrazol-4-yl]ethoxy}phenyl)imidazo[1,2-a]pyridin-3-yl]methyl}-N-methylcarbamate(40 mg, 27%). The product was taken onto the next step without fullcharacterisation

Step 2

According to the general method for Boc deprotection (method B), givetert-butylN-{[6-(4-fluoro-2-{2-[3-(methoxymethyl)-1,5-dimethyl-1H-pyrazol-4-yl]ethoxy}phenyl)imidazo[1,2-a]pyridin-3-yl]methyl}-N-methylcarbamate(40 mg, 0.074 mmol) was dissolved in dioxane (2 mL) and treated with asolution of HCl in ether (2M, 2 mL). The solution stirred at roomtemperature for 3 hr and was evaporated under reduced pressure. Thecrude product dissolved in water and freeze dried to give the titlecompound as a light brown solid (20.1 mg, 62%). hplc rt 5.1 min LC-MSMH⁺ 438; ¹H NMR (400 MHz, DMSO-d₆) δ 9.84 (s, 2H), 9.20 (s, 1H), 8.43(s, 1H), 8.03 (dd, 2H), 7.76 (dd, 1H), 7.12 (dd, 2H), 6.98 (td, 1H),4.91 (s, 2H), 4.18 (s, 2H), 4.10 (t, 2H), 3.64 (s, 3H), (t, 2H), 3.15(s, 3H), 2.78 (t, 2H), 2.61 (s, 3H), 2.03 (s, 3H).

Example 104

2-[6-(2-{2-[1,5-dimethyl-3-(morpholine-4-carbonyl)-1H-pyrazol-4-yl]ethoxy}-4-fluorophenyl)imidazo[1,2-a]pyridin-3-yl]ethan-1-amineStep 1

A solution of4-(2-{2-[3-(2-{[(tert-butoxy)carbonyl]amino}ethyl)imidazo[1,2-a]pyridin-6-yl]-5-fluorophenoxy}ethyl)-1,5-dimethyl-1H-pyrazole-3-carboxylicacid (Example 93 step 2, 80 mg, 0.15 mmol) in THF (2 mL) was treatedwith triethylamine (0.04 mL, 0.30 mmol), morpholine (0.02 mL, 0.22mmol), hydroxybenztriazole (25.5 mg, 0.19 mmol) and EDCI (36 mg, 0.19mmol), The reaction mixture was stirred at rt for 16 hrs with partialconversion. Further charges of each reagent were added and the mixturestirred again overnight., diluted with ethyl acetate and washed withsat. NaHCO₃, water and brine, dried over sodium sulphate andconcentrated. The crude product was purified by prep TLC (3% MeOH/DCM)to give tert-butylN-(2-{6-[2-(2-{1,5-dimethyl-3-[(morpholin-4-yl)carbonyl]-1H-pyrazol-4-yl}ethoxy)-4-fluorophenyl]imidazo[1,2-a]pyridin-3-yl}ethyl)carbamateas a light brown solid (40 mg, 44%). ¹H NMR (400 MHz, CDCl₃) δ 8.10 (s,1H), 7.55 (d, 1H), 7.46 (s, 1H), 7.20 (m, 1H), 6.79 (dd, 1H), 6.75-6.70(m, 2H), 5.28 (s, 1H), 5.25 (s, 1H), 4.17 (t, 2H), 3.65 (s, 3H), 3.48(t, 2H), 3.08 (t, 3H), 1.87 (s, 3H), 1.40 (d, 9H).

Step 2

According to the general method for Boc deprotection (method Btert-butylN-(2-{6-[2-(2-{1,5-dimethyl-3-[(morpholin-4-yl)carbonyl]-1H-pyrazol-4-yl}ethoxy)-4-fluorophenyl]imidazo[1,2-a]pyridin-3-yl}ethyl)carbamate(40 mg, 0.066 mmol) was dissolved in a solution of HCl in ether (2M, 5ml). The solution stirred at room temperature for 4 hr and wasevaporated under reduced pressure. The crude product dissolved in waterand freeze dried to give the title compound as a light brown solid (20mg, 61%). hplc rt 4.6 min LC-MS MH⁺ 507; ¹H NMR (400 MHz, DMSO-d₆) δ8.95 (s, 1H), 8.20 (br. s, 2H), 8.15 (s, 1H), 8.01 (dd, 2H), 7.57 (dd,1H), 7.17 (dd, 1H), 6.97 (td, 1H), 4.14 (t, 2H), 3.71 (s, 3H), 3.54 (m,8H), 3.19 (q, 2H), 2.88 (t, 2H), 2.07 (s, 3H).

Example 105

4-(2-{2-[3-(2-aminoethyl)imidazo[1,2-a]pyridin-6-yl]-5-fluorophenoxy}ethyl)-N-(2-methoxyethyl)-1,5-dimethyl-1H-pyrazole-3-carboxamideStep 1

A solution of4-(2-{2-[3-(2-{[(tert-butoxy)carbonyl]amino}ethyl)imidazo[1,2-a]pyridin-6-yl]-5-fluorophenoxy}ethyl)-1,5-dimethyl-1H-pyrazole-3-carboxylicacid (Example 93 step 2, 80 mg, 0.15 mmol) in THF (2 mL) was treatedwith triethylamine (0.04 mL, 0.30 mmol), 2-methoxyethylamine (0.019 mL,0.22 mmol), hydroxybenztriazole (25 mg, 0.19 mmol) and EDCI (36 mg, 0.19mmol). The reaction mixture was stirred at rt for 16 hrs, with partialconversion. Another charge of each reagent was added and the mixturestirred again at rt for 20 hr. The reaction was quenched with sat.NaHCO₃, and extracted with EtOAc. The organic layer was washed withwater and brine, dried over sodium sulphate and concentrated. The crudeproduct was purified by prep TLC (3% MeOH/DCM) to give tert-butylN-(2-{6-[4-fluoro-2-(2-{3-[(2-methoxyethyl)carbamoyl]-1,5-dimethyl-1H-pyrazol-4-yl}ethoxy)phenyl]imidazo[1,2-a]pyridin-3-yl}ethyl)carbamateas a light brown solid (35 mg, 40%). ¹H NMR (400 MHz, DMSO-d₆) δ 8.34(s, 1H), 7.78 (t, 1H), 7.50 (d, 1H), 7.45 (m, 2H), 7.22 (d, 1H), 7.13(d, 1H), 6.98 (t, 1H), 6.86 (dd, 1H), 4.14 (t, 2H), 3.75 (s, 3H), 3.39(t, 2H), 3.25-3.20 (m, 5H), 3.02 (m, 4H), 1.90 (s, 3H), 1.30 (d, 9H).

Step 2

According to the general method for Boc deprotection (method B),tert-butylN-(2-{6-[4-fluoro-2-(2-{3-[(2-methoxyethyl)carbamoyl]-1,5-dimethyl-1H-pyrazol-4-yl}ethoxy)phenyl]imidazo[1,2-a]pyridin-3-yl}ethyl)carbamate(35 mg, 0.059 mmol) was dissolved in a solution of HCl in ether (2M, 5mL). The solution stirred at room temperature for 4 hr and wasevaporated under reduced pressure. The crude product dissolved in waterand freeze dried to give the title compound as a light brown solid (30mg, 90%). hplc rt 4.8 min LC-MS MH⁺ 495; ¹H NMR (400 MHz, DMSO-d₆) δ14.8 (br.s, 1H), 8.95 (s, 1H), 8.20-8.15 (m, 4H), 8.02 (dd, 2H), 7.78(d, 1H), 7.56 (td, 1H), 7.22 (dd, 2H), 6.96 (td, 1H), 4.15 (t, 2H), 3.71(s, 3H), 3.46 (t, 2H), 3.39 (m, 2H), 3.33 (t, 2H), 3.25 (m, 5H), 3.04(t, 2H), 2.06 (s, 3H).

Example 106

2-{6-[2-(2-{1,5-dimethyl-3-[(methylamino)methyl]-1H-pyrazol-4-yl}ethoxy)-4-fluorophenyl]imidazo[1,2-a]pyridin-3-yl}ethan-1-amineStep 1

A solution of tert-butylN-{2-[6-(4-fluoro-2-{2-[3-chloro-1,5-dimethyl-1H-pyrazol-4-yl]ethoxy}phenyl)imidazo[1,2-a]pyridin-3-yl]ethyl}carbamate(Example 100 Step 1, 340 mg, 0.63 mmol)) in acetonitrile (7 mL) wastreated potassium carbonate (173 mg, 1.23 mmol) followed by methylaminesolution (2M in THF, 0.078 mmol, 2.5 mmol). The reaction mixture wasstirred at rt for 16 hr, diluted with EtOAc, washed with sat. NaHCO₃solution and brine, dried over sodium sulphate and concentrated. Thecrude product was purified by prep TLC using 5% MeOH/DCM to givetert-butylN-(2-{6-[2-(2-{1,5-dimethyl-3-[(methylamino)methyl]-1H-pyrazol-4-yl}ethoxy)-4-fluorophenyl]imidazo[1,2-a]pyridin-3-yl}ethyl)carbamate (300 mg, 89%). ¹H NMR (400MHz, DMSO-d₆) δ 8.36 (s, 1H), 7.52 (d, 1H), 7.44 (t, 1H), 7.41 (s, 1H),7.26 (d, 2H), 7.07 (td, 1H), 7.01 (dd, 1H), 6.88 (td, 1H), 4.08 (m, 3H),3.58 (s, 3H), 3.52 (t, 2H), 3.32 (t, 2H), 3.17 (s, 3H), 3.04 (t, 2H),2.79 (t, 2H), 2.25 (s, 3H), 1.95 (s, 3H), 1.30 (s, 9H).

Step 2

According to the general method for Boc deprotection (method B),tert-butylN-(2-{6-[2-(2-{1,5-dimethyl-3-[(methylamino)methyl]-1H-pyrazol-4-yl}ethoxy)-4-fluorophenyl]imidazo[1,2-a]pyridin-3-yl}ethyl)carbamate (30 mg, 0.056 mmol) wasdissolved in dioxane (2 ml), cooled at 0° C., and treated with asolution of HCl in ether (2M, 4 ml). The solution stirred at roomtemperature for 3 hr and was evaporated under reduced pressure. Thecrude product dissolved in water and freeze dried to give the titlecompound as a light brown solid (10 mg, 41%). hplc rt 4.2 min LC-MS MH⁺437; ¹H NMR (400 MHz, DMSO-d₆) δ 14.7 (br.s, 1H), 9.01 (m, 2H), 8.28(br. s, 2H), 8.15 (s, 1H), 8.09 (d, 1H), 8.02 (d, 2H), 7.57 (td, 1H),7.13 (dd, 2H), 6.98 (td, 1H), 4.10 (t, 2H), 3.94 (t, 2H), 3.68 (s, 3H),3.47 (t, 2H), 3.21 (t, 2H), 2.86 (t, 2H), 2.06 (s, 3H).

Example 107

N-{[4-(2-{2-[3-(2-aminoethyl)imidazo[1,2-a]pyridin-6-yl]-5-fluorophenoxy}ethyl)-1,5-dimethyl-1H-pyrazol-3-yl]methyl}-N-methylacetamideStep 1

A solution of tert-butylN-(2-{6-[2-(2-{1,5-dimethyl-3-[(methylamino)methyl]-1H-pyrazol-4-yl}ethoxy)-4-fluorophenyl]imidazo[1,2-a]pyridin-3-yl}ethyl)carbamate (Example 106 Step 1, 100 mg,0.19 mmol) in DCM (3 mL) was cooled at 0° C. before dropwise addition oftriethylamine (0.052 mL, 0.37 mmol) followed by acetyl chloride (0.02mL, 0.28 mmol). The reaction mixture was warmed to rt for 2 hr, dilutedwith DCM washed with sat.NaHCO₃ solution and brine, dried over sodiumsulphate and concentrated under reduced pressure. The crude product waspurified by prep TLC (5% MeOH/DCM) to give tert-butylN-(2-{6-[2-(2-{1,5-dimethyl-3-[(N-methylacetamido)methyl]-1H-pyrazol-4-yl}ethoxy)-4-fluorophenyl]imidazo[1,2-a]pyridin-3-yl}ethyl)carbamate(17 mg, 16%), which was taken on without further purification.

Step 2

According to the general method for Boc deprotection (method B),tert-butylN-(2-{6-[2-(2-{1,5-dimethyl-3-[(N-methylacetamido)methyl]-1H-pyrazol-4-yl}ethoxy)-4-fluorophenyl]imidazo[1,2-a]pyridin-3-yl}ethyl)carbamate(17 mg, 0.07 mmol) was dissolved in dioxane (2 mL), cooled to 0° C. andtreated with a solution of HCl in ether (2M, 4 mL). The solution stirredat room temperature for 3 hr and was evaporated under reduced pressure.The crude product dissolved in water and freeze dried to give the titlecompound as a light brown solid (10 mg, 71%). hplc rt 3.7 min LC-MS MH⁺479; ¹H NMR (400 MHz, DMSO-d₆) δ 14.6 (br.s, 1H), 8.96 (s, 1H),8.15-8.05 (m, 4H), 8.00 (d, 1H), 7.55 (td, 1H), 7.11 (dd, 1H), 6.97 (td,1H), 4.17 (s, 2H), 3.98 (t, 2H), 3.62 (s, 3H), 3.20 (q, 2H), 2.82 (s,3H), 2.76 (t, 2H), 2.05 (s, 3H), 1.90 (s, 3H).

Example 108

N-{[4-(2-{2-[3-(2-aminoethyl)imidazo[1,2-a]pyridin-6-yl]-5-fluorophenoxy}ethyl)-1,5-dimethyl-1H-pyrazol-3-yl]methyl}-N-methylmethanesulfonamideStep 1

A solution of tert-butylN-(2-{6-[2-(2-{1,5-dimethyl-3-[(methylamino)methyl]-1H-pyrazol-4-yl}ethoxy)-4-fluorophenyl]imidazo[1,2-a]pyridin-3-yl}ethyl)carbamate (Example 106 Step 1, 100 mg,0.19 mmol) in DCM (3 mL) was cooled at 0° C. before dropwise addition oftriethylamine (0.052 mL, 0.37 mmol) followed by mesyl chloride (0.022mL, 0.28 mmol). The reaction mixture was warmed to rt for 2 hr, dilutedwith DCM, washed with sat.NaHCO₃ solution and brine, dried over sodiumsulphate and concentrated under reduced pressure. The crude product waspurified by prep TLC (5% MeOH/DCM) to give tert-butylN-(2-{6-[2-(2-{1,5-dimethyl-3-[(N-methylmethanesulfonamido)methyl]-1H-pyrazol-4-yl}ethoxy)-4-fluorophenyl]imidazo[1,2-a]pyridin-3-yl}ethyl)carbamate(10 mg, 9%) which was carried onto the next step without fullcharacterization.

Step 2

According to the general method for Boc deprotection (method B)tert-butylN-(2-{6-[2-(2-{1,5-dimethyl-3-[(N-methylmethanesulfonamido)methyl]-1H-pyrazol-4-yl}ethoxy)-4-fluorophenyl]imidazo[1,2-a]pyridin-3-yl}ethyl)carbamate(10 mg, 0.016 mmol) was dissolved in dioxane (2 ml) cooled at 0° C. andtreated with a solution of HCl in ether (2M, 3 ml). The solution stirredat room temperature for 3 hr and was evaporated under reduced pressure.The crude product dissolved in water and freeze dried to give the titlecompound as a light brown solid (4 mg, 48%). hplc rt 5.1 min LC-MS MH⁺515; ¹H NMR (400 MHz, DMSO-d₆) δ 14.6 (br.s, 1H), 8.92 (s, 1H),8.13-8.05 (m, 4H), 7.97 (d, 1H), 7.55 (dd, 1H), 7.10 (dd, 1H), 6.97 (td,1H), 4.08 (t, 2H), 4.02 (s, 2H), 3.65 (s, 3H), 3.43 (t, 2H), 3.19 (q,2H), 2.88 (s, 3H), 2.81 (t, 2H), 2.59 (s, 3H), 2.07 (s, 3H).

The following Example compounds are made in analogous methods toExamples 1 to 108.

Details of Biological Assays, and Data

(a)

The IC₅₀ values of Example compounds of the invention for Plasmodiumvivax (Pv) NMT, Human NMT1 and Human NMT2 were measured using asensitive fluorescence-based assay based on detection of CoA by7-diethylamino-3-(4-maleimido-phenyl)-4-methylcoumarin, as described inGoncalves, V., et al., Analytical Biochemistry, 2012, 421, 342-344 andGoncalves, V., et al., J. Med. Chem, 2012, 55, 3578. An adapted versionof the assay was used to measure the IC₅₀ values of Plasmodiumfalciparum (PfNMT), Plasmodium berghei (PbNMT), Leishmania donovani(LdNMT), Leishmania major (LmNMT), and Trypanosoma brucei (TbNMT) forcertain compounds of the invention. For PfNMT, PbNMT, LmNMT, LdNMT andTbNMT the final enzyme concentration and peptide substrates aremodified, see below:

-   -   PfNMT Final Concentration: 500 ng/mL    -   PbNMT Final Concentration: 400 ng/mL    -   LmNMT Final Concentration: 400 ng/mL    -   LdNMT Final Concentration: 400 ng/mL    -   TbNMT Final Concentration: 500 ng/mL    -   PfNMT, PbNMT, LmNMT and LdNMT Peptide Substrate: Homo sapiens        p60^(src) (2-16) Amino Acids, final concentration 4.0 μM,        Sequence: GSNKSKPKDASQRRR-NH₂, as in PvNMT.    -   TbNMT Peptide Substrate: Plasmodium falciparum ARF (2-16) amino        acids final concentration 4.0 μM Sequence: GLYVSRLFNRLFQKK-NH₂.

NMT IC₅₀ values for Example compounds of the invention are provided inthe table of FIGS. 1A-C.

(b)

EC₅₀ values for Plasmodium falciparum (Pf) NMT were measured for certaincompounds of the invention using an assay utilising SYBR Green dye. Theassay was carried out as follows:

Synchronous Plasmodium falciparum 3D7 late stage trophozoites at 33-36 hwere used. Final parasitemia and haematocrit were between 0.1-0.2% and2% respectively. Red blood cells used for the assay were centrifuged toremove the buffy coat and washed twice in Roswell Park MemorialInstitute (RPMI) Media 1640 so that no white blood cells were present.The culture medium contained RPMI 1640 with 5 g/L Albumax, 0.025 g/Lgentamycin and 0.292 g/L L-glutamine.

Sterile 96 well black tissue culture plates (Costar) were used routinelyfor every assay. Drugs were diluted in culture medium and used induplicate wells for each dilution ranging from 10.000, 3.333, 1.111,0.370, 0.123, 0.041 and 0.014 μM respectively in a final volume of 100μL per well. Chloroquine was used as a standard with ten times reducedconcentrations range as above. Two sets of control were used induplicate wells, one set with no added drugs (positive control) and onewith uninfected red blood cells (negative control).

The plates were incubated at 37° C. for 48 h in a gas chamber flushedwith 5% CO₂, 5% 02 and 90% N₂. After 48 h supernatants were taken outfrom each well and replaced with fresh drug and incubated for a further48 h in the same manner. At the end of the 96 h incubation, 25 μL ofSYBR Green I dye (SYBR Green I nucleic acid gel stain 10000×, in DMSOfrom Invitrogen) in lysis buffer (1 μL dye to 1 mL lysis buffer) wasadded to each well and stored overnight at −20° C. The lysis buffercontained Tris (20 mM, pH 8.0), EDTA (2 mM), Saponin (0.16%) and TritonX-100 (1.6% v/v).

Plates were warmed to room temperature and fluorescence intensity wasmeasured with a FLUOstar Omega Microplate fluorescence reader (BMGLabtech). Values were expressed in relative fluorescence units. Bindingof SYBR Green is specific for parasite DNA as mature erythrocytes lackDNA and RNA. Fluorescence intensity unit was converted to percentage (%)of growth as follows:

% growth=(culture under drug)−(uninfected RBC)/(culture with nodrug)−(uninfected RBC)×100

and the EC₅₀ value was determined.

The Plasmodium falciparum (Pf) NMT EC₅₀ values for certain Examplecompounds of the invention are provided in the table of FIGS. 1A-C.

(c)

Mouse Malaria Model Protocol Day 0

Blood from a donor mouse infected with Plasmodium berghei, GFP ANKA 507clone 1 strain at a parasitemia of 10% is collected using a 26G 10 mmneedle containing 50 μL Heparin (200 u/ml). From this suspension, 1×10⁶parasites in 200 μL PBS is delivered through intra-peritoneal injectionusing a 26G 10 mm needle and a 1 ml syringe into 3-4 naive mice pertreatment group.

Day 3-6

72, 96, 120 and 144 hours post-infection, the experimental groups aretreated with the compounds (5-50 mg/kg in 200 μL PBS) twice daily forfour days either by intra-peritoneal injection or oral gavage. Thedosage is partly determined by a preliminary toxicity test(pre-experiment). For intra-peritoneal injection, mice are injected onthe right side using a 26G 10 mm needle and a 1 ml syringe. For oralgavage, mice are dosed using a 22G 38 mm oral dosing needle and a 1 mlsyringe. Simultaneous controls of PBS only (2×200 μL) and CQ (2×45 mg/kgin 200 μL PBS for intra-peritoneal injection or 2×60 mg/kg in 200 μL PBSfor oral gavage) are also conducted. Other routes of application arepossible. A blood smear to determine parasite load is performed daily(from day 3 onwards) by taking a drop of tail blood and staining theblood smear with Giemsa. 8-10 fields with 1000-2000 total RBCs arecounted and the number of cells infected with parasites is determined.Percentage parasitemia is then determined for both control andexperimental groups.

The percentage reduction in the parasite burden for mice treated withcertain Example compounds of the invention over control mice isindicated in the table of FIGS. 1A-C.

(d)

Metabolic Activity Assay (MTS Assay)

Example NMT inhibitors of the invention were tested for activity in anin vitro metabolic activity assay using human cell lines (HeLa andBL-41). Compounds having activity in inhibiting metabolic activity inthe assay are expected to be useful as agents for preventing and/ortreating cancer, by virtue of being inhibitors of human NMT1 and/orNMT2.

Cell Preparation:

Hela cells were grown in DMEM media (supplemented with 10% FBS) andseeded in a 96-well plate 24 h prior to treatment. BL-41 cells weregrown in RPMI-1640 media (supplemented with 10% FBS) and seeded directlybefore treatment. Cell suspensions were prepared by adjusting the celldensity to the appropriate concentration (as stated in the table below)and 50 μL of the cell suspension was transferred to wells B-G in columns2-11 of a 96-well plate.

Number of Cells Plated.

Hela BL-41 Cell suspension 16,000 700,000 concentration (cells/mL) cellsper well 800 35,000

Assay Procedure:

100 μL of growth media containing 0.2% DMSO was added to wells B-G incolumns 2 and 11 as positive controls and 100 μL of growth mediacontaining Puromycin (3 μg/mL; final concentration in the plate 2 μg/mL)was added to wells B-G in column 3 as a negative control. 7concentrations of inhibitor solution were prepared using example NMTinhibitors (same final percentage of DMSO, dilution factor=3 startingfrom 15 μM or 150 μM) and 100 μL of inhibitor solution was added towells B-G in columns 4-10 (final concentration of example NMT inhibitorin the plate starting from 10 μM or 100 μM; total volume of thewells=150 μL). The plate was incubated at 37° C. with 5% CO₂ level forHeLa cells and 10% CO₂ for BL-41 cells. A representation of a typical96-well plate is shown in FIG. 2 .

After 72 h, 20 μL MTS reagent (Promega, prepared according to thesupplier protocol) was added to each well of the 96-well plate. Theplate was incubated at 37° C. (2 hours for HeLa cells and 4 hours forBL-41 cells) and absorbance was measured at 490 nm with a Spectra MaxM2/M2e microplate reader. The average absorbance value of the negativecontrol (Puromycin-treated cells) was subtracted from each value and themetabolic activity was calculated as a percentage relative to thepositive control (DMSO-treated cells). EC₅₀s were calculated usingGrafit 7.0 (Erithacus Software Ltd, UK).

Each of the compounds tested showed activity in the metabolic activityassay, having an EC₅₀ value of less than 5 μM, and indicating that thecompounds are useful as anti-cancer agents. EC₅₀ values for example NMTinhibitors of the invention are shown in the table of FIG. 1 (for theBL-41 cell results) and FIG. 3 (for the HeLa cell results).

(e)

Rhinovirus Production Assay

Example 30 of the invention was tested for activity in an in vitrorhinovirus production assay using the human HeLa Ohio cell line. Theresults are shown in FIG. 4 . Compounds having activity in inhibitingrhinovirus production in the assay are expected to be useful as agentsfor preventing and/or treating asthma or chronic obstructive pulmonarydisease (COPD), by virtue of being inhibitors of human NMT1 and/or NMT2,which are thought to myristoylate rhinovirus capsid subunit VP4 and beessential for virus assembly.

Cell Preparation and Infections:

Hela Ohio cells were grown in growth media (DMEM supplemented with 10%FBS, 1% Sodium Bicarbonate and 25 mM Hepes) and seeded 24 h prior toinfection in a 12-well plate at a cell density allowing to obtain 100%confluent cells (5.95×10¹ cells per well) the next day. Confluent cellswere treated with different concentrations of inhibitor, as indicated inthe table below, each in triplicate. The Example 30 inhibitor solutionwas prepared by serial dilutions in growth media and the DMSO controlcontained the same percentage of DMSO as in the solution with thehighest concentration of inhibitor. The cell media was replaced by 1 mlper well of the inhibitor dilution and the plate was incubated for 6 hat at 37° C. with 5% CO₂. Cells were then infected with HRV16 at an MOIof 1 in the presence of the inhibitor. The virus stock (2.492×10⁷PFU/ml) was diluted in growth media to obtain a virus solution at5.95×10⁵ PFU/ml. This virus dilution was used to dilute the inhibitor aspreviously described in order to obtain virus solutions with theinhibitor concentrations indicated in the table below. The cell mediawas as replaced by 1 ml per well of virus+inhibitor solution and theplate was incubated for 1 h at room temperature to allow virusadsorption onto the cells. The cells were then washed with PBS and themedia was replaced with 1 ml per well of growth media+inhibitor,prepared as previously described. After 16 h of incubation at 37° C.with 5% CO₂, the plate was frozen at −80° C. and submitted to 2 cyclesof freezing-thawing to release the virus from the cells. The media andcells form each well were then transferred to 1.5 ml tubes andcentrifuged for 1 min at 16000×g to remove cell debris.

Concentrations of Inhibitor

Concentrations of inhibitor (nM) 2000 1000 500 200 20 2 0 (DMSO Control)

Virus Titre Assay:

The virus titres from the cleared supernatants were determined bymeasuring the 50% Tissue Culture Infective Dose (TCID₅₀). Each samplewas diluted in a series of 10-fold dilutions in TCID₅₀ media (DMEMsupplemented with 2% FBS, 1% Sodium Bicarbonate, 25 mM Hepes and 1%Penicillin-Streptomycin) and 50 μl of each of the dilutions 1/10 to1/10⁻⁸ were added onto a 96-well plate, in 6 replicates. HeLa Ohio cellsat a cell density of 1×10⁵ cells/mi in TCID₅₀ media were then added toeach well (150 μl per well). Some wells with cells alone (withoutsample) were included as control. The plates were then incubated for 96h at 37° C. with 5% CO₂. The appearance of characteristic cytopathiceffect, compared to control cells, was then assessed by observation ofthe plates on an inverted microscope and the virus titres weresubsequently calculated by the method of Reed and Muench.

The experiment was performed in triplicate and mean values+/−SD areshown in FIG. 4 .

(f)

Rhinovirus Production Assay 2

Examples 30, 35, 49 and 50 of the invention was tested for activity in arhinovirus replication assay in the human HeLa Ohio cell line. Theresults are shown in FIGS. 5 a to 5 c . Compounds having activity ininhibiting rhinovirus production in the assay are expected to be usefulas agents for preventing and/or treating asthma or chronic obstructivepulmonary disease (COPD), by virtue of being inhibitors of human NMT1and/or NMT2, which are thought to myristoylate rhinovirus capsid subunitVP4 and be essential for virus assembly.

Cell Preparation and Infections:

HeLa Ohio cells were grown in growth media (DMEM supplemented with 10%FBS, 1% Sodium Bicarbonate and 25 mM Hepes) and seeded 24 hours prior toinfection in a 96-well plate at a cell density allowing to obtain 100%confluent cells (5.6×10⁴ cells per well) the next day.

Confluent cells were infected with HRV16 at an MOI of 0.05 in thepresence of different concentrations of inhibitor, as indicated in thetable below, each in duplicate. The virus stock (5.6×10⁶ PFU/ml) wasdiluted in growth media to obtain a virus solution at 1.4×10⁴ PFU/ml.This virus dilution was used to dilute the inhibitor by serial dilutionsin order to obtain virus solutions with the inhibitor concentrationsindicated in the table below. The DMSO control contained the samepercentage of DMSO as in the solution with the highest concentration ofinhibitor. The cell media was as replaced by 200 μl per well ofvirus+inhibitor solution and the plate was incubated for 48 hours at 37°C. with 5% CO₂.

Cells with the same inhibitor dilutions but without virus were used inparallel to control for compound cytotoxicity.

Concentrations of inhibitor (nM) 500 250 125 50 25 10 5 2 1 0.5 0 (DMSOControl)

Cell Viability Assay:

The number of viable cells was determined 48 hours post-infection usingthe CellTiter 96® AQ_(ueous) One Solution Cell Proliferation Assay(Promega) according to the manufacturer's instructions. Briefly, thevolume of the media was adjusted to 100 μl/well and 20 μl of CellTiter96*AQ_(ueous) One Solution Reagent was added to each well. The plateswere incubated for a further 2 to 4 hours at 37° C. with 5% CO₂ andabsorbance at 490 nm was measured using a 96-well plate reader (FLUOstarOmega). The percentage of virus-induced cytopathic effect (% CPE) wascalculated with the following equation:

% CPE=100×OD_(490 nm) [(uninfected compound treated control−infectedcompound treated test sample)/(uninfected compound treatedcontrol−infected DMSO treated control)].

Cytotoxicity of the compounds was evaluated by determining the cellviability of the compound-treated uninfected cells, expressed as apercentage of the DMSO-treated control.

The results are shown in FIGS. 5 a to 5 c : FIGS. 5 a and 5 b show thevirus-induced cytopathic effect (CPE) measured by a Metabolic ActivityAssay (MTS assay) 2 days post-infection; FIG. 5 c shows the cellviability of the inhibitor-treated but uninfected cells, measured inparallel by MTS 2 days post-treatment. The result show that Examples 30,35, 49 and 50 inhibit HRV16 production in a dose-dependent manner,without affecting cell viability.

(g)

Plasmodium Liver Stage Assay

This assay is a slightly modified version of the assay previouslydescribed in Meister, S. Imaging of Plasmodium liver stages to drivenext-generation antimalarial drug discovery Science, 2011, vol. 334,pages 1372-1377.

HepG2-A16-CD81EGFP cells stably transformed to express a GFP-CD81 fusionprotein were cultured at 37° C. in 5% CO2 in DMEM (Invitrogen, Carlsbad,Calif., USA) supplemented with 10% FCS, 0.29 mg/mL glutamine, 100 unitsof penicillin, and 100 μg/mL streptomycin. The cells were seeded 24 hprior to infection into 1536-well plates at 3000 cells/well. The cellswere pretreated for 12 h with the drug in a 12-point dilution series,and the cells were then infected with freshly dissected P. bergheisporozoites expressing luciferase (1000 sporozoites/well). After 48 h ofincubation, the viability of P. berghei exoerythrocytic forms (EEF) wasmeasured by bioluminescence. EC₅₀ values were obtained using themeasured bioluminescence intensity and a nonlinear variable slopefour-parameter regression curve fitting model in Prism 6 (GraphPadSoftware Inc.).

The P. berghei liver stage assay EC₅₀ (μM) values for certain Examplecompounds of the invention are provided in the table of FIG. 1 .

The compounds of Examples 1-101 exhibit one or more of the following:

(i) inhibition of Plasmodium falciparum (Pf)N-myristoyl transferase inthe range of IC₅₀ 0.00001 to 99.9 μM in assay (a);

(ii) inhibition of Plasmodium vivax (Pv)N-myristoyl transferase in therange of IC₅₀ 0.00001 to 99.9 μM in assay (a);

(iii) inhibition of Plasmodium berghei (Pb)N-myristoyl transferase inthe range of IC₅₀ 0.00001 to 99.9 μM in assay (a);

(iv) inhibition of Leishmania donovani (Ld)N-myristoyl transferase inthe range of IC₅₀ 0.001 to 99.9 μM in assay (a);

(v) inhibition of Leishmania major (Lm)N-myristoyl transferase in therange of IC₅₀ 0.001 to 99.9 μM in assay (a);

(vi) inhibition of Trypanosoma brucei (Tb)N-myristoyl transferase in therange of IC₅₀ 0.001 to 99.9 μM in assay (a);

(vii) inhibition of Plasmodium falciparum (Pf strains 3D7 or NF54) inthe range of EC₅₀ 0.001 to 10 μM in assay (b) (Selected examples 1-43were tested against the 3D7 strain while subsequent compounds, wereassessed against the NF54 strain).

(viii) reduction in the parasite burden in the mouse malaria model(Plasmodium berghei) following twice daily intraperitonealadministration at 10 mg/kg in the range 10-100%;

(ix) inhibition of metabolic activity in HeLa cells in the range of EC₅₀0.001 to 10 μM in assay (d);

(x) inhibition of metabolic activity in BL-41 cells in the range of EC₅₀0.001 to 10 μM in assay (d).

(xii) inhibition of Plasmodium berghei liver stage in the range of EC₅₀0.00001 to 10 μM in assay (g);

(xii) inhibition of viral replication in in the range of EC₅₀ 0.001 to10 μM in assay (e) or (f), and preferably inhibition of viralreplication in in the range of EC₅₀ 0.001 to 10 μM in assay (e) or (f)whilst having no effect on uninfected cells over the same timescale ofthe experiment.

Certain compounds of Examples 1-101 also exhibit inhibitory activity forHuman N-myristoyl transferase 1 and/or Human N-myristoyl transferase 2in the range of IC₅₀ 0.00001 to 99.9 μM.

Preferred Example compounds of the invention are those which exhibitinhibitory activity at lower concentrations within the IC₅₀ range shownabove. For example, the compounds of examples 7, 8, 9, 17, 18, 20, 22,24, 29, 30, 31, 32, 33, 35, 36, 39, and 48, exhibit IC₅₀ at Plasmodiumfalciparum (Pf)N-myristoyl transferase in the range of IC₅₀ 0.00001 to0.1 μM in assay (a).

Preferred Example compounds of the invention are those which exhibitinhibitory activity at lower concentrations within the IC₅₀ range shownabove. For example, the compounds of examples 2, 3, 4, 6, 7, 8, 9, 10,11, 12, 13, 17, 18, 19, 20, 22, 23, 24, 26, 28, 29, 30 and 32, 33, 34,35, 36, 37, 38, 39, 41, 42, 43, 45, 46, 48, 49, 50, 53, 55, 56, 57, 58,60, 62, 63, 66, 67, 68, 69, 70, 71, 72, 74; 75, 76, 77, 78, 79, 80, 81,82, 86, 86, 88, 89, 90, 91, 92, 93, 94, 95, 96 exhibit IC₅₀ atPlasmodium vivax (Pv)N-myristoyl transferase in the range of IC₅₀0.00001 to 0.1 μM in assay (a).

Preferred Example compounds of the invention are those which exhibitinhibitory activity at lower concentrations within the IC₅₀ range shownabove. For example, the compounds of Examples 7 and 8 exhibit IC₅₀ atLeishmania donovani (Ld)N-myristoyl transferase in the range of IC₅₀0.001 to 0.1 μM in assay (a).

Preferred Example compounds of the invention are those which exhibitinhibitory activity at lower concentrations within the IC₅₀ range shownabove. For example, the compound of Example 8 exhibits IC₅₀ atLeishmania major (Lm)N-myristoyl transferase in the range of IC₅₀ 0.001to 0.1 μM in assay (a).

Preferred Example compounds of the invention are those which exhibitinhibitory activity at lower concentrations within the IC₅₀ range shownabove. For example, the compound of Example 7 exhibits IC₅₀ atTrypanosoma brucei (Tb)N-myristoyl transferase in the range of IC₅₀0.001 to 0.1 μM in assay (a).

Preferred Example compounds of the invention are those which exhibitinhibitory activity at lower concentrations within the IC₅₀ range shownabove. For example, the compounds of Examples 7, 8, 17 and 18 exhibitIC₅₀ at Plasmodium berghei (Pb)N-myristoyl transferase in the range ofIC₅₀ 0.00001 to 0.1 μM in assay (a).

The example compounds of the invention for which EC₅₀ values forPlasmodium falciparum (Pf) were measured using assay (b) all showed EC₅₀for Plasmodium falciparum (Pf) in the range of EC₅₀ 0.001 to 10 μM. Someof those examples exhibited inhibitory activity at lower concentrationswithin the EC₅₀ range shown above. Preferred example compounds of theinvention are those which exhibit inhibitory activity at lowerconcentrations within the EC₅₀ range shown above. For example, examples7, 17.53, 56, 70, 77, 78, 85, 92, 94 exhibit EC₅₀ at Plasmodiumfalciparum (Pf 3D7 or NF54 strains) in the range of IC₅₀ 0.0001 to 0.1μM in assay (b).

The example compounds of the invention for which EC₅₀ values forPlasmodium berghei (Pb) in the liver stage of the diseases were measuredusing assay (g) all showed EC₅₀) in the range of EC₅₀ 0.001 to 10 μM.Some of those examples exhibited inhibitory activity at lowerconcentrations within the EC₅₀ range shown above. Preferred examplecompounds of the invention are those which exhibit inhibitory activityat lower concentrations within the EC₅₀ range shown above. For example,examples 8, 17, 18, 29, 30, 35, 37, 39, 53, 55, 56, 62, 68, 70, 72, 76and 92 exhibit EC₅₀ at Plasmodium berghei in the range of IC₅₀ 0.0001 to0.1 μM in assay (g).

The example compounds of the invention for which a reduction in parasiteburden in the mouse malaria model was measured using the protocoldescribed at (c) above all showed effects following twice-dailyadministration at 5 or 10 mg/kg/dose. Preferred example compounds of theinvention are those which lowered the parasite burden by more than 30%.For example, the examples 7, 17, 18 and 30 lowered the parasite burdenby more than 30% in the mouse malaria model.

The example compounds of the invention for which EC₅₀ values weremeasured in the metabolic activity assay (assay (d)) all showed EC₅₀ forHeLa and/or BL-41 cells in the range of EC₅₀ 0.01 to 10 μM. Some ofthose examples exhibited inhibitory activity at lower concentrationswithin the EC₅₀ range shown above. For example, examples 17, 18, 30, 49,50, 62, 63, 70, 76, 77, 83, 86, 94, 97, 100 exhibit EC₅₀ in the range offrom 0.001 to 1 μM in assay (d) for HeLa and/or BL-41 cells; andexamples 30, 49 and 50 exhibit EC₅₀ in the range of from 0.001 to 0.1 μMin assay (d) for HeLa and/or BL-41 cells.

Examples 30, 35, 49, and 50 of the invention for which EC₅₀ value wasmeasured in the rhinovirus assay (assay (e)) exhibited EC₅₀ in the rangeof from 0.01 to 0.1 μM.

1-69. (canceled)
 70. An inhibitor of N-myristoyl transferase (NMT) whichis a compound of formula (I) or a salt thereof,

wherein: Y is selected from the group consisting of —CH—, —C(R²)— and—N—; R¹ is a group of formula —X-L-A; X is selected from the groupconsisting of —O—, —N(H)— and —S—, or is absent; L is selected from thegroup consisting of —(CHR¹²)_(m)— and —(CHR¹²)_(m)O—, or is absent; m is1, 2 or 3; A is a 6-10-membered aromatic carbocycle or a 5-10-memberedaromatic heterocycle, said aromatic carbocycle or heterocycle beingoptionally substituted with 1, 2, or 3 substituents each independentlyselected from the group consisting of —F, —Cl, —Br, —OCH₃, —OCF₃, —CN,—C₁₋₆alkyl optionally substituted by up to 3 halogen, hydroxyl, or—OC₁₋₄alkyl groups, —S(O)C₁₋₄ alkyl, —S(O)₂C₁₋₄alkyl, —C(O)N(R⁹)₂,—C(O)N(R¹³)C₁₋₄alkylOC₁₋₄alkyl, —C(O)N(C₁₋₄alkylOC₁₋₄alkyl)₂,—CH₂C(O)N(R⁹)₂, —CH₂C(O)N(R¹³)C₁₋₄alkylOC₁₋₄alkyl,—CH₂C(O)N(C₁₋₄alkylOC₁₋₄alkyl)₂, —S(O)₂NHC₁₋₄alkyl, —S(O)₂N(C₁₋₄alkyl)₂,—NHC₁₋₄alkyl, —N(C₁₋₄alkyl)₂, —NHC(O)C₁₋₄alkyl, —NHC(O)CF₃,—NHS(O)₂C₁₋₄alkyl, CH₂N(R¹³)₂, CH₂N(R¹³)C(O)C₁₋₄alkyl,CH₂N(R¹³)S(O)₂C₁₋₄alkyl, —CH₂S(O)₂C₁₋₄alkyl, and CO₂H s is 0, 1, 2, or3; each R² is independently selected from the group consisting of —F,—Cl, —Br, —OCH₃, —OCF₃, —CN, —C₁₋₄alkyl optionally substituted by up to3 halogen or hydroxyl groups, —S(O)C₁₋₄alkyl, —S(O)₂C₁₋₄alkyl,—S(O)₂NHC₁₋₄alkyl, —S(O)₂N(C₁₋₄alkyl)₂, —NHC₁₋₄alkyl, —N(C₁₋₄alkyl)₂,—NHC(O)C₁₋₄alkyl, —NHC(O)CF₃, and —NHS(O)₂C₁₋₄alkyl; E, J and G are eachC(R⁷); K, Q and M are each nitrogen; q is 0 or 1; R³ is hydrogen ormethyl; R⁴ is hydrogen or methyl; R⁶ is hydrogen or C₁₋₆alkyl optionallysubstituted by up to 3 —F, —Cl, —Br, —OH, —OCH₃, —OCF₃ or —CN groups; R⁶is hydrogen or C₁₋₆alkyl optionally substituted by up to 3 —F, —Cl, —Br,—OH, —OCH₃, —OCF₃ or —CN groups; or the R⁵ and R⁶ groups and the N theyare bonded to form a 4 to 7 membered non-aromatic heterocycle, theheterocycle optionally comprising 1 or 2 further heteroatoms selectedfrom N, O and S, optionally substituted by up to 3 —F, —Cl, —Br, —OH,—OCH₃, —OCF₃ or —CN groups; when present R¹⁰ is hydrogen or methyl; whenpresent R¹¹ is hydrogen or methyl; or the R³ group and the R⁵ group andthe intervening atoms form a 3 to 7 membered non-aromatic heterocyclecomposed of the intervening atoms and bond, or the intervening atoms and—(CHR^(a))_(r)—; or the R¹⁰ group and the R⁵ group and the interveningatoms form a 3 to 7 membered non-aromatic heterocycle composed of theintervening atoms and —(CHR^(a))_(r)—; r is 1, 2, 3, 4 or 5; R^(a) ishydrogen or methyl; each R⁷ is independently selected from the groupconsisting of hydrogen, halogen, C₁₋₄alkoxy, and C₁₋₄alkyl optionallysubstituted with 1, 2 or 3 halogens; and R⁷ is selected from the groupselected from hydrogen and C₁₋₄alkyl; each R⁹ is independently selectedfrom the group consisting of hydrogen and C₁₋₄alkyl, or two R⁹ groupsand the N they are bonded to form a 4 to 7 membered non-aromaticheterocycle, the heterocycle optionally comprising 1 or 2 furtherheteroatoms selected from N, O and S; and each R¹² is independentlyselected from the group consisting of hydrogen, C₁₋₆alkyl optionallysubstituted by up to 3 —F, —Cl, —Br, I, —OH, —OCH₃, —OCF₃ or —CN groups,C₁₋₆alkenyl optionally substituted by up to 3 —F, —Cl, —Br, I, —OH,—OCH₃, —OCF₃ or —CN groups, and C₁₋₆alkynyl optionally substituted by upto 3 —F, —Cl, —Br, I, —OH, —OCH₃, —OCF₃ or —CN groups; and each R¹³ isindependently selected from the group consisting of hydrogen andC₁₋₄alkyl.
 71. The inhibitor of NMT as claimed in claim 70, wherein X isselected from the group consisting of —O—, —N(H)— and —S—; and/or L isselected from the group consisting of —(CHR¹²)_(m)— and —(CHR¹²)_(m)O—.72. The inhibitor of NMT as claimed in claim 70, wherein the compoundhas the formula (IA)


73. The inhibitor of NMT as claimed in claim 72, wherein Y is —CH—; X is—O—; L is —(CH₂)_(m); m is 1 or 2; A is an aromatic carbocycle orheterocycle selected from the group consisting of phenyl, pyridinyl,quinolinyl, imidazolyl, benzimidazolyl, pyrazolyl, thiazolyl,1,2,3-triazolyl and 1,2,4-triazolyl, wherein A is substituted with 1, 2,or 3 groups, and at least one of the substituents is —C(O)N(R⁹)₂,—C(O)N(R¹³)C₁₋₄alkylOC₁₋₄alkyl, —C(O)N(C₁₋₄alkylOC₁₋₄alkyl)₂,—CH₂C(O)N(R⁹)₂, —CH₂C(O)N(R¹³)C₁₋₄alkylOC₁₋₄alkyl,—CH₂C(O)N(C₁₋₄alkylOC₁₋₄alkyl)₂, —NHC(O)C₁₋₄alkyl, —NHC(O)CF₃,CH₂N(R¹³)C(O)C₁₋₄alkyl, CH₂N(R¹³)S(O)₂C₁₋₄alkyl, or CO₂H; q is 1; R⁷ ishydrogen or methyl; and R¹⁰ is hydrogen and R¹¹ is hydrogen.
 74. Theinhibitor of NMT as claimed in claim 73, wherein A is selected from thegroup consisting of substituted pyrazolyl and thiazolyl.
 75. Theinhibitor of NMT as claimed in claim 74, wherein A is substituted with1, 2, or 3 groups, and at least one of the substituents is C(O)N(R⁹)₂.76. The inhibitor of NMT as claimed in claim 72, wherein q is 1, R¹⁰ ishydrogen, R¹¹ is hydrogen, and A is 4-pyrazolyl, substituted by up to 3groups independently selected from the group consisting of —C₁₋₄alkyl;—CH₂OC₁₋₄alkyl, CF₂H, CF₃, C(O)N(Me)₂, —C(O)-1-pyrazole; and—C(O)-4-morpholine.
 77. The inhibitor of NMT as claimed in claim 70,wherein q is 1, R¹⁰ is hydrogen and R¹¹ is hydrogen.
 78. The inhibitorof NMT as claimed in claim 70, wherein A is an aromatic carbocycle orheterocycle selected from the group consisting of phenyl, pyridinyl,quinolinyl, imidazolyl, benzimidazolyl, pyrazolyl, thiazolyl,1,2,3-triazolyl and 1,2,4-triazolyl, said aromatic carbocycle orheterocycle being optionally substituted with 1, 2, or 3 groupsindependently selected from the group consisting of —C₁₋₄alkyl, whereineach —C₁₋₄alkyl is optionally substituted by up to 3 halogen, hydroxylor —OC₁₋₄alkyl groups; —C(O)N(R⁹)₂; —CH₂C(O)N(R⁹)₂;—C(O)N(R¹³)C₁₋₄alkylOC₁₋₄alkyl; —CH₂N(R¹³)₂ and CH₂N(R¹³)S(O)₂C₁₋₄alkyl.79. The inhibitor of NMT as claimed in claim 70, wherein Y is —CH— or—C(R²)—.
 80. The inhibitor of NMT as claimed in claim 70, wherein X is—O— and L is —(CH₂)_(m).
 81. The inhibitor of NMT as claimed in claim70, wherein R⁷ is hydrogen or methyl, and/or R⁷ is hydrogen or methyl.82. The inhibitor of NMT as claimed in claim 70 wherein A is substitutedwith 1, 2, or 3 groups, and at least one of the substituents is—C(O)N(R⁹)₂, —C(O)N(R¹³)C₁₋₄alkylOC₁₋₄alkyl,—C(O)N(C₁₋₄alkylOC₁₋₄alkyl)₂, —CH₂C(O)N(R⁹)₂,—CH₂C(O)N(R¹³)C₁₋₄alkylOC₁₋₄alkyl, —CH—₂C(O)N(C₁₋₄alkylOC₁₋₄alkyl)₂,—NHC(O)C₁₋₄alkyl, —NHC(O)CF₃, CH₂N(R¹³)C(O)C₁₋₄alkyl,CH₂N(R¹³)S(O)₂C₁₋₄alkyl, or CO₂H.
 83. The inhibitor of NMT as claimed inclaim 78, wherein A is an optionally substituted 5-thiazolyl.
 84. Theinhibitor of NMT as claimed in claim 83, wherein the compound has theformula (IA″)

and wherein: said 5-thiazolyl is optionally substituted with 1 or 2methyl groups; X is —O—; L is —(CH₂)_(m)—; m is 1, 2 or 3; R^(2′) ishydrogen, chlorine or fluorine; and R³ and R⁴ are each independentlyhydrogen or methyl; R⁵ and R⁶ are each independently hydrogen or methyl.85. The inhibitor of NMT as claimed in claim 78, wherein the compoundhas the formula (IA′″)

and wherein: X is —O— or absent; L is —(CH₂)_(m)—; m is 2 or 3; R^(2′)is hydrogen or fluorine; R² is hydrogen or —OCH₃; R³ and R⁴ are eachhydrogen; R⁵ and R⁶ are each methyl.
 86. The inhibitor of NMT as claimedin claim 70, wherein: X is —O—; L is —(CH₂)_(m)—; m is 1 or 2; A isselected from the group consisting of optionally substituted3-pyridinyl, 4-pyridinyl and 1-imidazolyl; s is 0; R³ and R⁴ are eachhydrogen; and R⁵ and R⁶ are each methyl.
 87. The inhibitor of NMT asclaimed in claim 70, which is selected from:(6-(4-fluoro-2-(2-(4-methylthiazol-5-yl)ethoxy)phenyl)-[1,2,4]triazolo[4,3-a]pyridin-3-yl)methanamine;(6-(4-fluoro-2-(2-(1,3,5-trimethyl-1H-pyrazol-4-yl)ethoxy)phenyl)-[1,2,4]triazolo[4,3-a]pyridin-3-yl)methanamine;1-(6-(4-fluoro-2-(2-(1,3,5-trimethyl-1H-pyrazol-4-yl)ethoxy)phenyl)-[1,2,4]triazolo[4,3-a]pyridin-3-yl)-N,N-dimethylmethanamine;1-(6-(4-fluoro-2-(2-(4-methylthiazol-5-yl)ethoxy)phenyl)-[1,2,4]triazolo[4,3-a]pyridin-3-yl)-N-methylmethanamine;1-(6-(4-fluoro-2-(2-(1,3,5-trimethyl-1H-pyrazol-4-yl)ethoxy)phenyl)-[1,2,4]triazolo[4,3-a]pyridin-3-yl)-N-methylmethanamine;1-(6-(4-chloro-2-(2-(4-methylthiazol-5-yl)ethoxy)phenyl)-[1,2,4]triazolo[4,3-a]pyridin-3-yl)-N,N-dimethylmethanamine1-(6-(4-chloro-2-(2-(1,3,5-trimethyl-1H-pyrazol-4-yl)ethoxy)phenyl)-[1,2,4]triazolo[4,3-a]pyridin-3-yl)-N,N-dimethylmethanamine;1-(6-(4-fluoro-2-(2-(3-isobutyl-1,5-dimethyl-1H-pyrazol-4-yl)ethoxy)phenyl)-[1,2,4]triazolo[4,3-a]pyridin-3-yl)-N,N-dimethylmethanamine;1-(6-(4-fluoro-2-(2-(5-isobutyl-1,3-dimethyl-1H-pyrazol-4-yl)ethoxy)phenyl)-[1,2,4]triazolo[4,3-a]pyridin-3-yl)-N,N-dimethylmethanamine;4-(2-{2-[3-(azetidin-3-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yl]-5-fluorophenoxy}ethyl)-1,3,5-trimethyl-1H-pyrazole;4-[2-(5-fluoro-2-{3-[(methylamino)methyl]-[1,2,4]triazolo[4,3-a]pyridin-6-yl}phenoxy)ethyl]-N,N,1,5-tetramethyl-1H-pyrazole-3-carboxamide;{[6-(2-{2-[1-(difluoromethyl)-3,5-dimethyl-1H-pyrazol-4-yl]ethoxy}-4-fluorophenyl)-[1,2,4]triazolo[4,3-a]pyridin-3-yl]methyl}(methyl)amine;{[6-(2-{2-[1,5-dimethyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]ethoxy}-4-fluorophenyl)-[1,2,4]triazolo[4,3-a]pyridin-3-yl]methyl}(methyl)amine;4-(2-{2-[3-(azetidin-3-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yl]-5-fluorophenoxy}ethyl)-N,N,1,5-tetramethyl-1H-pyrazole-3-carboxamide;4-[2-(5-fluoro-2-{3-[2-(methylamino)ethyl]-[1,2,4]triazolo[4,3-a]pyridin-6-yl}phenoxy)ethyl]-N,N,1,5-tetramethyl-1H-pyrazole-3-carboxamide;4-(2-{5-fluoro-2-[3-(pyrrolidin-2-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yl]phenoxy}ethyl)-1,3,5-trimethyl-1H-pyrazole;[2-(6-{4-fluoro-2-[2-(1,3,5-trimethyl-1H-pyrazol-4-yl)ethoxy]phenyl}-[1,2,4]triazolo[4,3-a]pyridin-3-yl)ethyl](methyl)amine;N-methyl[(6-{3-[2-(1,3,5-trimethyl-1H-pyrazol-4-yl)ethoxy]pyridin-2-yl}-[1,2,4]triazolo[4,3-a]pyridin-3-yl)methyl]amine;{[6-(2-{2-[1,5-dimethyl-3-(morpholine-4-carbonyl)-1H-pyrazol-4-yl]ethoxy}-4-fluorophenyl)-[1,2,4]triazolo[4,3-a]pyridin-3-yl]methyl}(methyl)amine;{[6-(2-{2-[1,5-dimethyl-3-(pyrrolidine-1-carbonyl)-1H-pyrazol-4-yl]ethoxy}-4-fluorophenyl)-[1,2,4]triazolo[4,3-a]pyridin-3-yl]methyl}(methyl)amine;[(6-{5-fluoro-3-[2-(1,3,5-trimethyl-1H-pyrazol-4-yl)ethoxy]pyridin-2-yl}-[1,2,4]triazolo[4,3-a]pyridin-3-yl)methyl](methyl)amine;

or a salt of any one thereof.
 88. A pharmaceutical composition whichcomprises the inhibitor of NMT as claimed in claim 70 and apharmaceutically acceptable carrier.
 89. A method of treating orpreventing a disease or disorder in which inhibition of N-myristoyltransferase provides a therapeutic or prophylactic effect in a mammal,which comprises administering to the mammal a therapeutically effectiveamount of the inhibitor of NMT as claimed in claim 70.